OBJECTIVES:To describe meropenem population pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation (ECMO) with or without renal replacement therapy (RRT), and to identify dosing regimens likely to achieve safe and effective exposures. METHODS:Serial blood samples were collected over a single dosing interval during ECMO. Total plasma concentrations were measured by a validated assay. Population pharmacokinetic modelling and Monte Carlo dosing simulations were performed using Monolix. Dosing regimens were assessed against efficacy targets (Cmin ≥2 or ≥8 mg/L) and a toxicity threshold (Cmin >45 mg/L). RESULTS:A total of 150 plasma concentration-time points were obtained from 18 patients. Meropenem pharmacokinetics were best described by a two-compartment model with first-order elimination. ECMO flow rate significantly influenced the volume of distribution of the central compartment, while estimated creatinine clearance and concomitant RRT significantly influenced drug clearance. Using the primary efficacy target of 2 mg/L, a meropenem dose of 1 g every 8 h as continuous infusion was the most appropriate regimen for patients with a creatinine clearance of 60-130 mL/min receiving ECMO at a flow rate of 4-6 L/min. In patients receiving RRT, this regimen demonstrated less than 4% probability of reaching toxic concentrations and 100% probability of achieving the efficacy target across all simulated scenarios. The regimen remained robust against the higher efficacy target of 8 mg/L in most scenarios. CONCLUSIONS:A meropenem dose of 1 g every 8 h as continuous infusion is safe and efficacious in most critically ill patients receiving ECMO with or without concomitant RRT.

Background and objectives:Poor aqueous stability limits the use of continuous infusion of intravenous (IV) amoxicillin in outpatient parenteral antimicrobial therapy. This study aimed to evaluate whether buffering improves amoxicillin stability and whether co-administration of probenecid enhances amoxicillin exposure. Methods:Amoxicillin solutions (4.17, 50, and 66.6 mg/mL) were prepared in 0.3% citrate-buffered saline (pH 7), water for injection, and 0.9% w/v saline, then stored at 2-8°C for 10 days, followed by 24 h at 32°C. Stability was assessed using a validated assay method and tested against the UK Yellow Cover Document (YCD) acceptance criteria. A population pharmacokinetic model was developed and used to perform Monte Carlo dosing simulations to evaluate the PTA (95% time above MIC) for various IV amoxicillin regimens, with and without probenecid. Results:Citrate buffering did not improve the stability of amoxicillin, and none of the tested conditions met YCD criteria. Co-administration of probenecid significantly increased the PTA for amoxicillin. Administration of 3-6 g of IV amoxicillin every 12 h, with 1 g of probenecid once daily, achieved ≥90% PTA against pathogens with MICs up to 4-8 mg/L depending on infusion durations. For MICs up to 16 mg/L, 4-6 g of IV amoxicillin every 12 h plus 2 g of probenecid once daily achieved a favourable PTA (>90%). Conclusions:Amoxicillin's aqueous instability was not resolved by citrate buffering. However, for patients requiring IV therapy, probenecid-boosted intermittent and extended infusion regimens of amoxicillin appear to be promising alternatives that warrant further clinical investigation.

Piperacillin-tazobactam is commonly used in critically ill pediatric patients; however, standard dosing regimens may not reliably achieve maximally effective exposures in this population. To characterize the population pharmacokinetics of piperacillin-tazobactam in critically ill pediatric patients and evaluate the adequacy of commonly used dosing regimens, plasma concentrations were obtained around a single dose of piperacillin-tazobactam in critically ill pediatric patients aged 1 month to 12 years. A simultaneous population pharmacokinetic model for piperacillin and tazobactam was developed using nonlinear mixed-effects modeling. Monte Carlo simulations were performed to assess the probability of target attainment (PTA) for short, extended, and continuous infusion regimens across a range of ages and renal function states. Dosing adequacy was defined by simultaneous attainment of target drug exposures for piperacillin (100%fT > MIC) and tazobactam (85%fT > 2 mg/L). Thirty-one patients contributed 102 plasma samples, of which only 22.6% of patients achieved simultaneous piperacillin-tazobactam target exposures, considering a piperacillin MIC of 16 mg/L. Renal function and infusion duration were the primary determinants of attainment of target attainment. Standard short infusions frequently failed to achieve combined target exposures, particularly in patients with preserved renal function or augmented renal clearance (ARC). Extended infusions improved PTA, but remained suboptimal at higher MICs. Continuous infusion consistently achieved the highest target drug exposures across all simulated scenarios. Short intermittent piperacillin-tazobactam infusions and even extended infusions often result in suboptimal exposure in critically ill pediatric patients. Continuous infusion represents a rational dosing strategy to improve combined target attainment, particularly in children with preserved or ARC.

OBJECTIVES:To characterize the population pharmacokinetics and pharmacokinetic/pharmacodynamic target attainment of piperacillin and tazobactam in critically ill patients with sepsis or septic shock in Malaysian intensive care units and to use the population pharmacokinetic model to estimate individual target attainment and explore associations with clinical outcomes. METHODS:Serial blood samples were collected on days 1 and 3 of therapy in this prospective multicentre study. Total plasma piperacillin and tazobactam concentrations were quantified using a validated chromatographic assay. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Monolix. Therapeutic exposure was defined as achieving 100% fT>16 mg/L for piperacillin and 85% fT>2 mg/L for tazobactam while remaining below the piperacillin toxicity threshold (<160 mg/L). RESULTS:Forty-five critically ill adults with sepsis or septic shock were recruited (median age, 61 years [range: 18-88]; median creatinine clearance (CLcr) 70 mL/min [range: 30-161]; 20 females). A one-compartment model with first-order elimination best described the pharmacokinetics for both drugs. Estimated CLcr significantly influenced drug clearance. Pre-defined therapeutic exposures were achieved in 54% and 44% on days 1 and 3, respectively. Patients attaining exposures were older and had lower CLcr. Clinical cure and ICU survival were numerically different across exposure groups, although these exploratory comparisons were not statistically significant. Simulations indicated that a 4.5 g loading dose followed by 4.5 g every 6 h as a continuous infusion achieved effective and safe exposures in patients with CLcr 50 to 130 mL/min. CONCLUSION:Continuous infusion is the most reliable strategy for achieving early piperacillin/tazobactam therapeutic exposures in patients with sepsis or septic shock.

Background:Outpatient parenteral antimicrobial therapy (OPAT) is practised worldwide due to the benefits it provides to patients and healthcare systems. However, its full potential remains unrealized due to different implementation challenges. This study aims to identify barriers and facilitators that influence the routine implementation of current practices in the OPAT programme. Methods:An international, multi-centre electronic survey was conducted among healthcare facilities providing OPAT services in Australia, Malaysia, the UK, Spain, Turkey and Middle East countries. The survey instrument was developed based on the Consolidated Framework for Implementation Research and guideline recommendations for OPAT. Statistical analyses were performed using SPSS version 30. Results:The survey received responses from 150 healthcare facilities across 10 countries offering OPAT services. The majority (11 879.7%) of healthcare facilities implement OPAT through a formal structure. The majority (92.2%) had a designated team lead. Most facilities (12 685.7%) reported the implementation of antimicrobial toxicity monitoring. Only 58 facilities (39.5%) reported implementation of regular audits of their OPAT programmes. The most reported barriers to OPAT implementation included wide geographic distribution of patients (50.7%), lack of financial support (42.7%) and the dosing frequency of antimicrobials (40.6%). Facilitators to OPAT implementation include hospital bed savings, clinical safety and efficacy, cost-effectiveness and patient satisfaction. Conclusions:The majority of healthcare facilities implement OPAT through a formal structure. However, several challenges continue to hinder its routine implementation. Ongoing efforts to address implementation barriers are crucial for strengthening existing services and supporting the expansion of new services.

BACKGROUND:Ceftaroline and ceftobiprole are fifth-generation cephalosporins with activity against methicillin-resistant Staphylococcus aureus. Like other β-lactam antimicrobials, their efficacy correlates with the percentage of the dosing interval during which unbound drug concentrations exceed the minimum inhibitory concentration (MIC) of the pathogen (% fT>MIC). However, achieving optimal exposures may be challenging in patients with altered pharmacokinetics or deep-seated infections. METHODS:A systematic review was performed using MEDLINE (Pubmed), Embase, Web of Science and Scopus libraries. Peer-reviewed studies reporting the pharmacokinetics of ceftaroline and ceftobiprole and/or their pharmacokinetics/pharmacodynamics in S. aureus infections were included. Screening, data extraction, and quality assessment were performed independently by two reviewers. RESULTS:Thirty-one studies for ceftaroline and 22 studies for ceftobiprole met the inclusion criteria. Literature appraisal revealed substantial pharmacokinetic variability in special populations, particularly critically ill patients, with increased volumes of distribution and variable clearance. In patients without severe infections, standard dosing generally achieved high probabilities of attaining pre-clinical pharmacokinetic/pharmacodynamic targets for bacteriostasis, 1-log₁₀ and 2-log₁₀ kill (20%, 26%, and 37% fT>MIC for ceftaroline, 8.8%, 13.5%, and 23% for ceftobiprole) up to the clinical breakpoints. By contrast, in patients with altered pharmacokinetics or deep-seated infections, intensified dosing and prolonged infusions were often required to achieve plasma and tissue pharmacokinetic/pharmacodynamic targets, particularly for stringent endpoints such as 100% fT>MIC. CONCLUSIONS:Ceftaroline and ceftobiprole pharmacokinetics are highly variable in hospitalized patients, potentially compromising attainment of stringent pharmacokinetic/pharmacodynamic targets for S. aureus infections. Intensified doses and prolonged infusions may therefore be necessary to ensure adequate drug exposure.

BACKGROUND:Approximately 10% of hospitalized patients globally report a penicillin allergy, leading to inappropriate antibiotic prescribing and inferior healthcare outcomes. Evidence supporting the effectiveness and widespread implementation of inpatient penicillin direct oral challenge (DOC) is limited. METHODS:A prospective, multicenter, international type 2 hybrid effectiveness-implementation study was conducted in 40 hospitals across 8 countries between November 2022 and May 2025. Adult inpatients with a penicillin allergy underwent assessment using a digital penicillin allergy toolkit (National Antibiotic Allergy Network [NAAN] App). According to site clinical practice, participants received penicillin DOC (effectiveness intervention) or assessment only. Participating sites received bimonthly audit and feedback at least 3 months after site activation (implementation strategy). Observational data were used to emulate a target trial to examine secondary effectiveness outcomes, including antibiotic prescribing at 90 days in DOC versus non-DOC participants. The primary implementation outcome was adoption of the NAAN App within 6 months of site activation. RESULTS:Among 5121 participants assessed, 1573 (30.7%) underwent DOC, of which 1502 (95.5%) were delabeled. Of 71 (4.5%) participants with a positive DOC, 6 (0.4%) had a serious adverse event. Of 1852 inpatients in the target trial analysis, 892 underwent DOC and 960 underwent assessment only. Participants who underwent DOC were more likely to be prescribed penicillin (risk ratio [RR], 13.25 [95% confidence interval {CI}, 7.82-22.46]), and less likely to be prescribed World Health Organization (WHO) "Watch" or "Reserve" antibiotics (RR, 0.73 [95% CI, .60-.89]) at 90 days post evaluation. Within 6 months of site activation, 77 clinicians adopted the NAAN App. CONCLUSIONS:Multidisciplinary adoption of inpatient penicillin DOC was safe and significantly improved penicillin prescribing and reduced use of WHO restricted antibiotics.

PURPOSE:Lumacaftor-ivacaftor (LI) is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator for patients with cystic fibrosis homozygous for the F508del-CFTR variant. All CFTR modulators, including LI, are metabolized in the liver, and their use in advanced cystic fibrosis-related liver disease (ACFRLD) is not recommended due to concerns of worsening liver impairment, despite potential benefits for nutrition and lung function. METHODS:A pilot study was conducted at the Queensland Children's Hospital, Australia, to describe the pharmacokinetics of LI and its metabolites (ivacaftor-M1 and ivacaftor-M6) in pediatric patients with ACFRLD. Three patients aged 4, 10, and 18 years with ACFRLD received 2 weeks of half-dose LI followed by 2 weeks of full-dose LI with weekly liver function monitoring and pharmacokinetic sampling on week 2 and 4. Stool samples were also obtained. A single stool sample was obtained from 28 children taking LI without ACFRLD as a control group. FINDINGS:Liver function remained stable for patients with ACFRLD, although one patient developed hyperammonemia at week 3 and ceased LI with resolution of hyperammonemia. In patients with ACFRLD, plasma concentrations of ivacaftor and lumacaftor were decreased, whereas M1 and M6 were elevated compared with reported values. Stool concentrations of ivacaftor were increased, lumacaftor and M1 decreased, and M6 variable compared with controls. IMPLICATIONS:These findings suggest reduced ivacaftor absorption and impaired biliary excretion in ACFRLD, contributing to elevated M1, M6, and decreased lumacaftor concentrations. Pharmacokinetic variability in ACFRLD highlights the potential role of individualized profiling to support safe and effective CFTR modulator treatment in this population. Queensland Children's Hospital Human Research and Ethics Committee (HREC/19/QCHQ/53788); Australian New Zealand Clinical Trials Registry (ACTRN12619001347156).

Although inappropriate therapy has been consistently associated with adverse outcomes, the magnitude and consistency of the benefit associated with appropriate empiric therapy in critically ill patients remain uncertain. We aimed to quantify the prevalence of appropriate empiric antimicrobial therapy and evaluate its association with outcomes and antimicrobial exposure in a large international ICU cohort. This predefined sub-analysis of the DIANA study included adult ICU patients receiving empirical antimicrobials for suspected or confirmed bacterial infection. Only patients with microbiologically confirmed infections were analyzed, and therapy was classified as appropriate if at least one agent demonstrated in vitro activity against the identified pathogen. Associations with 28-day mortality and antimicrobial-free days were assessed using multivariable logistic and Cox regression models. Pre-specified interaction analyses explored effect modification by disease severity and diagnostic certainty. Of 845 patients with microbiologically confirmed infections, 87.7

Physiological alterations in patients with sepsis and trauma can influence antibiotic clearance, yet reliable predictors remain poorly defined. We aimed to investigate the determinants of piperacillin and cefazolin clearance in these populations to identify bedside indicators of subtherapeutic exposure. Prospective physiological and pharmacokinetic study in patients receiving piperacillin/tazobactam for sepsis or prophylactic cefazolin post-trauma. Patients also received intravenous sinistrin. Intensive pharmacokinetic sampling, cardiac output (CO) monitoring and four urinary creatinine clearance (uCLCR) measurements were performed. Data were analysed with non-compartmental pharmacokinetic methods, and linear and logistic regression. We enrolled 49 septic and 28 trauma patients. Trauma patients were younger (33.5 vs. 46.5 years) and had higher uCLCR (155.5 vs. 107.5 mL/min). Linear regression identified that lower Sequential Organ Failure Assessment scores and an hyperdynamic state with higher CO and 2 and 8-h uCLCR were the strongest predictors of increased piperacillin total clearance; higher 2-h uCLCR and hypoalbuminemia were the main predictors for cefazolin total clearance. Sinistrin CL was a weak predictor. Logistic regression identified augmented renal clearance (8-h uCLCR > 130 mL/min) as the main risk factor for piperacillin subtherapeutic exposure (OR 10.9, p < 0.05), also when defined using the Cockcroft–Gault cut-off of 114.5 mL/min from ROC analysis. In sepsis, low sickness severity and a hyperdynamic state with high cardiac output lead to increased uCLCR and high piperacillin clearance. In trauma, high cefazolin clearance occurs in the presence of an elevated uCLCR and hypoalbuminemia. These bedside physiological indicators, along with Cockcroft–Gault CLCR, may serve as early indicators of risk for subtherapeutic exposure.

OBJECTIVES:The aims of this study were to characterise the population pharmacokinetics (PK) of polymyxin B and to identify rational dosing strategies for Malaysian hospitalised patients. METHODS:Enrolled patients received a polymyxin B loading dose of 2.5 mg/kg of total body weight (TBW) followed by a maintenance dose of 1.25-1.5 mg/kg TBW every 12 h. Serial blood samples were collected and assayed using validated ultra-high performance liquid chromatography-tandem mass spectrometry method. Population PK modelling and Monte Carlo dosing simulations were performed using Monolix. RESULTS:Twenty-nine patients were included with a mean (SD) age of 51 (14) y old, TBW of 71 (22) kg, and estimated Cockcroft-Gault creatinine clearance of 68 (58) mL/min. A two-compartment model adequately described the data with TBW as a covariate for volume of distribution of central compartment. The population PK parameter estimates for drug clearance, volume of distribution of central compartment, volume of distribution of peripheral compartment, and inter-compartmental clearance were 1.6 L/h, 6.86 L, 10.76 L, and 11.97 L/h, respectively. Simulations showed that a fixed loading dose of 150 mg followed by a fixed maintenance dose of 75 mg every 12 h achieved optimal probability of target attainment against pathogens with an MIC of ≤1 mg/L and demonstrated the best balance between safety and efficacy for patients weighing 50-90 kg. CONCLUSIONS:Our findings suggest that current weight-based dosing regimens recommended by International Consensus Guidelines may expose some patients to an increased risk of nephrotoxicity. A fixed-dose strategy (150 mg or 200 mg loading dose followed by 75 mg every 12 h) should be considered in this patient population.

OBJECTIVES:Critically ill infants and children often experience subtherapeutic cefotaxime exposure when administered licenced doses. Dose individualization guided by model informed precision dosing (MIPD) software is emerging, however, external validation of MIPD performance before implementing into clinical practice is necessary. This in silico study assessed the accuracy of an MIPD software in predicting cefotaxime concentrations among critically ill infants and children using the a priori ('empiric') and the a posteriori (Bayesian forecasting) approaches. METHODS:The study population was between 1 month and 12 years of age receiving cefotaxime in a paediatric intensive care unit. Essential data was inputted into the MIPD software ID-ODSTM to perform the a priori (4 h and 6 h post dose) and the a posteriori (one- and two-measured serum cefotaxime concentrations) predictions. The concentrations predicted by ID-ODS were compared against measured concentrations, using bias, precision and linear regression methods. RESULTS:Thirty infants and children with 115 concentration measurements produced 194 simulations for analysis. The median age, weight and serum creatinine concentration were 22.8 months, 10.6 kg and 23 µM/L, respectively. The a priori approach showed high biases, low precisions, and significant underprediction [weighted mean prediction error (WMPE) -48.48%, -85.63%, weighted root mean squared prediction error (WRMSE) 98.86, 87.60% at 4 h and 6 h, respectively]. The a posteriori approach exhibited improved accuracy (WMPE 0.28%, -21.54%, WRMSE 76.41%, 58.98% for one and two samples, respectively). MIPD-guided dose adjustments achieved pre-defined PK-PD targets in >90% of simulations using the a posteriori approach. CONCLUSIONS:MIPD incorporating measured blood samples of cefotaxime increases the likelihood of achieved target drug concentrations in treating severe infections among critically ill infants and children.

BACKGROUND:Critically ill patients exhibit altered pharmacokinetics, rendering antibiotic dosing challenging. Achieving therapeutic antibiotic exposures may be improved with the use of precision dosing software programs. OBJECTIVES:To quantify and compare both a priori and a posteriori predictive performance of an antibiotic precision dosing software program in a heterogenous cohort of critically ill adults with infection. METHODS:The precision dosing program, ID-ODSTM, was used to predict a priori and a posteriori concentrations for piperacillin, meropenem, cefepime, flucloxacillin and vancomycin using clinical and demographic data derived from a previous study in critically ill adults (GUIDE trial). Predicted concentrations were compared to observed concentrations using pre-specified acceptance criteria (median predictive error (MDPE) ≤20% and median absolute predictive error (MDAPE) ≤30%), along with F20 and F30 metrics. Furthermore, the impact of predictions on theoretical dosing recommendations to achieve pre-defined drug exposures was assessed. RESULTS:The a priori predictive performance in 81 patients administered beta-lactams did not meet any pre-specified acceptance criteria (pooled MDPE -35% and MDAPE 58%). However, all beta-lactams met accuracy acceptance criteria for the a posteriori approach (pooled MDPE -3.6%), although only cefepime demonstrated acceptable precision and F20 and F30 acceptance. In 25 patients administered vancomycin, a priori predictive performance met all acceptance criteria for accuracy and precision.When assessing a priori theoretical dosing recommendation concordance, approximately one in three predictions led to an unnecessary dosing action. Concordance was similar with an a posteriori approach, however, overprediction was observed in 20% of meropenem predictions. CONCLUSIONS:In a heterogenous adult ICU population, the a priori predictive performance of vancomycin was shown to be acceptable. Conversely, the a priori predictive performance for the beta-lactams was not acceptable. Although predictive performance improved with the a posteriori approach for beta-lactams, only cefepime met acceptance criteria.

Optimal dosing of vancomycin in critically ill patients receiving renal replacement therapy (RRT) is uncertain due to high pharmacokinetic variability. We aimed to develop individualised vancomycin dosing recommendations that optimise efficacy while minimising toxicity. Prospective, international, pharmacokinetic study enrolling critically ill patients treated with vancomycin and various RRT modalities. A population pharmacokinetic model was developed, externally validated and applied to perform Monte Carlo dosing simulations. We calculated the probability of each dosing regimen to achieve the efficacy target against methicillin-resistant Staphylococcus aureus (ratio of the area under the concentration–time curve to the minimum inhibitory concentration (AUC0-24 h/MIC) ≥ 400) without exceeding the toxicity threshold (AUC0-24 h ≥ 700 mg.h/L). We enrolled 65 critically ill patients from 6 countries receiving continuous RRT (50.8

BACKGROUND:Therapeutic drug monitoring (TDM) may help optimize beta-lactam antibiotic dosing in patients with deep-seated infections. However, its impact on clinical outcomes remains unclear. OBJECTIVE:The objective of this review was to evaluate the existing evidence on the role of TDM and pharmacokinetic/pharmacodynamic (PK/PD)-guided optimization of beta-lactam antibiotic dosing in achieving PK/PD targets, and improving clinical outcomes in patients with deep-seated infections. METHODS:We conducted a systematic review of studies reporting on beta-lactam TDM, PK/PD target attainment, and clinical outcomes in adult (≥18 years) patients with confirmed deep-seated infections, including complex bacteraemias with a suspected or proven deep-seated source, infective endocarditis, bone and joint infection, and epidural abscess. The search was conducted using MEDLINE (via PubMed), Embase, CINAHL and CENTRAL from inception to June 2025. RESULTS:Twelve studies were included in the final analysis. Considerable variability was observed in PK/PD target definitions and attainment, dosing adjustments and outcome reporting. Eleven of the twelve studies were rated as poor quality on the Newcastle-Ottawa Scale due to lack of comparability. Only one study included a non-TDM comparator group and the authors reported no significant difference in clinical outcomes. Three studies showed a trend towards improved clinical outcomes with TDM-guided dosing. TDM frequently led to dose reductions due to concerns of beta-lactam antibiotic toxicity with standard dosing. CONCLUSION:Current evidence supporting beta-lactam antibiotic TDM in deep-seated infections is limited by methodological heterogeneity and poor study quality. Well-designed trials are needed to establish the clinical utility of TDM in this setting.