Background Management of E faecium bloodstream infections (BSIs) remains debated, particularly the clinical impact of vancomycin resistance, the role of follow-up cultures, and optimal therapeutic regimens. This study aimed to reach expert consensus on these unresolved clinical domains and identify priorities for future research. Methods We first conducted a systematic review and meta-analysis in January 20, 204 focusing on four predefined areas: mortality in E faecium BSIs compared with other BSIs, mortality in vancomycin-resistant enterococci (VRE)-BSIs compared with vancomycin-susceptible enterococci-BSIs, management of catheter-related E faecium BSIs, and 4) optimal antibiotic therapy for VRE-BSIs. These results informed a three-round Delphi process involving a panel of experts. An iterative approach was adopted: 16 initial questions developed from the systematic review (6-point Likert scale) were refined across rounds based on expert feedback. Consensus was defined as at least 80% agreement or disagreement. Findings 13 statements were generated across three broader domains. Regarding clinical outcomes and diagnostics, experts agreed that mortality is heavily influenced by comorbidities; thus, therapeutic assessment should rely on clinical trends and inflammatory markers, with follow-up blood cultures used to confirm eradication. Catheter-related BSI should be managed with device removal and short-course (<7 days) antibiotics in selected uncomplicated cases. For therapeutic management, teicoplanin is preferred for vanB VRE-BSI. For vanA VRE-BSI, both linezolid and high-dose daptomycin (>9 mg/kg per day) are effective, reserving daptomycin-based combinations for challenging cases (deep-seated infections and/or high Minimum Inhibitory Concentrations). Finally, future trials evaluating the impact of antimicrobial therapy should use Desirability-of-Outcome-Ranking analysis; the in-vitro potential of oritavancin justifies targeted randomized trials to define its clinical efficacy in VRE-BSI. Interpretation This paper delineates current evidence and expert consensus on management of E faecium BSI while identifying crucial knowledge gaps to guide future clinical research. Funding None.

PurposeEarly detection of steatotic liver disease (SLD) is critically important. In clinical practice, hepatic steatosis is frequently diagnosed using computed tomography (CT) performed for unrelated clinical indications. An equation for estimating magnetic resonance proton density fat fraction (MR-PDFF) using liver attenuation on non-contrast CT exists, but no equivalent equation exists for post-contrast CT. We sought to (1) determine whether an automated workflow can accurately measure liver attenuation, (2) validate previously identified optimal thresholds for liver or liver-spleen attenuation in post-contrast studies, and (3) develop a method for estimating MR-PDFF (FF) on post-contrast CT. MethodsThe fully automated TotalSegmentator 'total' machine learning model was used to segment 3D liver and spleen from non-contrast and post-contrast CT scans. Mean attenuation was extracted from liver (L) and spleen (S) volumes and from manually placed regions of interest (ROIs) in multi-phase CT scans of two cohorts: derivation (n = 1740) and external validation (n = 1044). Non-linear regression was used to determine the optimal coefficients for three phase-specific (arterial, venous, delayed) increasing exponential decay equations relating post-contrast L to non-contrast L. MR-PDFF was estimated from non-contrast CT and used as the reference standard. ResultsThe mean attenuation for manual ROIs versus automated volumes were nearly perfectly correlated for both liver and spleen (r > .96, p < .001). For moderate-to-severe steatosis (L < 40 HU), the density of the liver (L) alone was a better classifier than either liver-spleen difference (L-S) or ratio (L/S) on post-contrast CTs. Fat fraction calculated using a corrected post-contrast liver attenuation measure agreed with non-contrast FF > 15% in both the derivation and external validation cohort, with AUROC between 0.92 and 0.97 on arterial, venous, and delayed phases. ConclusionAutomated volumetric mean attenuation of liver and spleen can be used instead of manually placed ROIs for liver fat assessments. Liver attenuation alone in post-contrast phases can be used to assess the presence of moderate-to-severe hepatic steatosis. Correction equations for liver attenuation on post-contrast phase CT scans enable reasonable quantification of liver steatosis, providing potential opportunities for utilizing clinical scans to develop large scale screening or studies in SLD.

PURPOSE Taxane-induced peripheral neuropathy (TIPN) is a dose-limiting toxicity of paclitaxel in patients with cancer. TIPN prediction is challenging although patients with higher systemic paclitaxel exposure have higher TIPN risk. This study aimed to identify protein predictors of TIPN and paclitaxel pharmacokinetics (PK). METHODS This is a retrospective analysis of a prospective study of females with early-stage breast cancer receiving weekly paclitaxel. TIPN was assessed using the sensory subscale of the European Organisation for Research and Treatment of Cancer QLQ-Chemotherapy-Induced Peripheral Neuropathy (CIPN)20 (CIPN8). A blood sample was collected within 10 minutes before the end of the first paclitaxel infusion to measure plasma proteins using liquid chromatography-mass spectrometry and to estimate maximum systemic paclitaxel concentration ( C max ). A second sample was collected approximately 24 hours after the first infusion to estimate paclitaxel time above threshold ( T c >0.05 ). Linear mixed-effect and regression models were used to identify proteins predictive of TIPN and paclitaxel PK parameters, respectively, using a Bonferroni-adjusted α = .0006. RESULTS Data from 36 participants were included in the analysis testing associations of 83 proteins with TIPN or PK. Higher levels of complement C3 were associated with more severe TIPN trajectories ( P = .0002). No proteins were associated with either C max or T c >0.05 (all P > .0006). CONCLUSION Complement C3 concentration at the end of initial paclitaxel infusion may be useful for identifying patients with breast cancer and potentially other tumor types who could benefit from TIPN prevention strategies to improve long-term treatment outcomes.

BACKGROUND:Daptomycin is a once-daily lipopeptide antibiotic with a narrow therapeutic window. As higher doses (8-12 mg/kg) are increasingly used to treat resistant gram-positive infections, achieving therapeutic exposure while minimizing toxicity has become critical. Understanding daptomycin therapeutic drug monitoring (TDM) and what sampling strategy may be most precise and feasible are key to guiding appropriate dosing. The primary objective of this study was to ascertain the precision and bias of a mid-point sample area under the curve over 24-h (AUC24) determination compared to a peak and trough sample AUC24 determination using both simple calculation-based methods and a Bayesian model versus no TDM. METHODS:Adult patients receiving daptomycin with at least three steady-state concentrations (peak, mid-point, trough) were included in this analysis. A previously published one-compartment population pharmacokinetic model was applied using Bayesian estimation (Monolix Suite 2024R1). AUC24 values were estimated using all three concentrations (AUCref), and then re-estimated using individual samples (peak, mid-point, or trough) or paired samples (peak + trough). Performance of each strategy was evaluated using regression analysis with the coefficient of determination for precision (R2) and mean bias. RESULTS:The cohort included 210 patients (60% male) with a mean (range) age of 66 (18-91) years, body weight 78 (41-140) kg, and BMI 27 (14-51) kg/m2. A total of 880 daptomycin concentrations were analyzed in patients receiving a mean (range) daptomycin dose of 9 (5-17) mg/kg. The mean (range) AUC24 was 869 (385-1692) mg·h/L; only 45.7% of patients achieved the target range of 666 to 939 mg·h/L. A single mid-point sample had similar correlation to AUC24 (R2 = 0.57) as trough-only (R2 = 0.55), and greater precision than peak-only (R2 = 0.44). Bayesian estimation with two samples (peak + trough) provided the highest accuracy (R2 = 0.87) and lowest bias. CONCLUSIONS:A mid-interval sampling strategy offers a practical alternative to traditional TDM for daptomycin, enabling more consistent AUC estimation when full sampling is not feasible. A two-sample Bayesian approach remains the most accurate, supporting broader implementation of individualized daptomycin dosing.

Daptomycin dosing in pediatrics has not been updated since initial approval to align with contemporary adult dosing recommendations. We observed lower than anticipated exposures with median 24-hour area under the curve of 378 mg·h/L [interquartile range (IQR): 368–413] in 4 children despite use of high doses (17–20 mg/kg/d). There is a critical need to reappraise daptomycin dosing in pediatric patients for Staphylococcus aureus bloodstream infections.

BACKGROUND:Acute kidney injury (AKI) is a common condition affecting a significant portion of hospitalized and critically ill patients. Current AKI diagnosis relies on serum creatinine (sCr), which has several recognized limitations that impact the timely detection and response to AKI management. Serum cystatin C (sCys) has characteristics that can overcome the limitations of sCr, but head-to-head comparisons of these biomarkers is difficult to study prospectively. A quantitative assessment of the kinetics of sCys and sCr during AKI is necessary to support clinical workflow implementation for AKI diagnosis and management. METHODS:A quantitative systems pharmacology (QSP) model was developed using MATLAB and Simbiology (The MathWorks, Natick, MA), to simulate the concentration-time profiles of sCr and sCys under varying degrees of AKI across a spectrum of baseline kidney function. The model incorporated parameters from existing literature and used a contemporary sCr and sCys GFR equation to assess the time to reach AKI diagnostic criteria for both biomarkers. RESULTS:The model demonstrated that sCys achieves steady-state concentration and meets AKI diagnostic thresholds significantly faster than sCr, with an advantage of six to 48 hours, depending on CKD stage. sCys exhibited greater sensitivity in detecting GFR reductions, with the ability to detect AKI within 12-24 hours post-AKI, compared to 12-72 hours for sCr. The study also identified that for sCys, absolute value diagnostic cutoffs are more effective than percentage-based thresholds and can provide consistent detection across different CKD stages. CONCLUSION:sCys has superior kinetics for early AKI detection compared to sCr, making it a valuable addition to AKI diagnostic protocols, particularly in high-risk populations. Daily monitoring of sCys in patients at risk for AKI would facilitate more timely detection and potentially improve clinical outcomes. Future research should focus on validating sCys diagnostic criteria and integrating it with other biomarkers to enhance AKI management.

IntroductionExperts suggest doxorubicin clearance is decreased in women with a body mass index (BMI) of ≥35 kg/m2. However, few data support this recommendation.MethodsWomen receiving doxorubicin for breast cancer in three BMI groups were recruited (n = 15). Doxorubicin dosing was determined by body surface area and was administered by 30-min intravenous infusion. Blood samples were obtained at 0 h (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 5, 12-24, and 24-72 h following the beginning of infusion. Concentrations of doxorubicin and its metabolite, doxorubicinol, were assayed by LC-MS/MS. Non-compartment analysis was done using PKanalix2021R2 for pharmacokinetic (PK) analyses.ResultsThe median [range] BMI and age were 30.3 [23.5-57] kg/m2 and 53 [31-69] years. Thirteen of the 15 women had samples available for analysis. Four of the 13 had a BMI ≥ 35.0 kg/m2. PK parameters ranged from 37.8% (AUC0-inf) to 91.0% (Vd). Doxorubicinol PK parameters ranged from 37.8% (Cmax) to 67.6% (AUC0-inf). The average doxorubicinol:doxorubicin AUClasts ratio was 0.26 (range: 0.04-0.88). A t-test didn't suggest a significant difference in individual PK parameters (BMI < 35 kg/m2 vs. ≥35.0 kg/m2). The two highest clearances (380 L/h and 250 L/h) had a BMI ≥ 35.0 kg/m2; also, the highest clearance (1114 L/h) for doxorubicinol was ≥35.0 kg/m2.ConclusionsLarge interindividual variabilities in doxorubicin PK were observed in women up to a BMI of 57 kg/m2 and a total body weight of 141.5 kg. Women with a BMI ≥ 35.0 kg/m2 and breast cancer did not appear to have lower clearances of doxorubicin.ClinicalTrials.gov IDNCT01537029.

Background: Acute kidney injury (AKI) is a common condition affecting a significant portion of hospitalized and critically ill patients. Current AKI diagnosis relies on serum creatinine (sCr), which has several recognized limitations that impact the timely detection and response to AKI management. Serum cystatin C (sCys) has characteristics that can overcome the limitations of sCr, but head-to-head comparisons of these biomarkers is difficult to study prospectively. A quantitative assessment of the kinetics of sCys and sCr during AKI is necessary to support clinical workflow implementation for AKI diagnosis and management. Methods: A quantitative systems pharmacology (QSP) model was developed using MATLAB and Simbiology (The MathWorks, Natick, MA), to simulate the concentration-time profiles of sCr and sCys under varying degrees of AKI across a spectrum of baseline kidney function. The model incorporated parameters from existing literature and used a contemporary sCr and sCys GFR equation to assess the time to reach AKI diagnostic criteria for both biomarkers. Results: The model demonstrated that sCys achieves steady-state concentration and meets AKI diagnostic thresholds significantly faster than sCr, with an advantage of six to 48 hours, depending on CKD stage. sCys exhibited greater sensitivity in detecting GFR reductions, with the ability to detect AKI within 12-24 hours post-AKI, compared to 12-72 hours for sCr. The study also identified that for sCys, absolute value diagnostic cutoffs are more effective than percentage-based thresholds and can provide consistent detection across different CKD stages. Conclusion: sCys has superior kinetics for early AKI detection compared to sCr, making it a valuable addition to AKI diagnostic protocols, particularly in high-risk populations. Daily monitoring of sCys in patients at risk for AKI would facilitate more timely detection and potentially improve clinical outcomes. Future research should focus on validating sCys diagnostic criteria and integrating it with other biomarkers to enhance AKI management.

Fluids sampled from the gastrointestinal (GI) tract are of interest for evaluating the bioequivalence of oral medications, and more generally for evaluating GI-related diseases, and for profiling the individual gut microbiome. Existing options for capturing multiple fluid samples from specific locations in the GI tract are limited and invasive, particularly for the small intestine. Here, we report the development of an ingestible capsule for the collection of multiple fluid samples along the GI tract; we additionally report the use of data from sensors within the capsule to determine the sampling regions. The capsule has an ingestible size of Φ14 × 42 mm3. Within this volume, it includes three separate cartridges that capture and retain samples within capillaries; a stepper motor for positioning the sampling cartridges at a sampling port; a 3-axis accelerometer that enables a new method of correlating sample location; a microcontroller with wireless communication and sensor data storage capabilities; and batteries to power the device. We describe in vitro characterization and in vivo tests performed with canine models that have successfully verified the capabilities of the capsule. Fluid samples from the stomach, small intestine, and colon regions of the GI tract are identified by inertial measurements taken within the capsule, and correlated to measurements of the concentration of mesalamine (a drug used for testing) and the bile salt profile in each region, respectively.

While dual-energy X-ray absorptiometry (DEXA) is the gold standard for measuring lean body weight (LBW), computed tomography (CT) provides muscle composition and distribution metrics that can refine LBW for better weight-based dosing. We explored how existing computed tomography (CT) images could be utilized to better estimate LBW. Sixty-three adult patients (71.4

BACKGROUND:Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are breakthrough medicines for obesity treatment and have rapidly gained widespread clinical application. Although GLP-1RAs are generally not associated with drug-drug interactions (DDIs) via drug metabolism or transporter pathways, their effects on reduced gastrointestinal (GI) motility could influence the pharmacokinetics of coadministered oral medications. OBJECTIVES:This study uses physiologically based pharmacokinetic (PBPK) modeling to evaluate the DDI potential of GLP-1RA-induced GI motility delays. METHODS:Using Certara's Simcyp™ Simulator V23, we modeled the pharmacokinetics of atorvastatin, metformin, metoprolol, ethinyl estradiol, and digoxin in a virtual cohort of obese adults (n = 1000). GLP-1RA-related gastric emptying delays were simulated based on capsule endoscopy data from liraglutide-treated patients. Results were compared with clinical data from semaglutide and liraglutide users. Additionally, exploratory analyses were conducted on frequently coadministered drugs identified from the 2022 Medical Expenditure Panel Survey, including rosuvastatin and dabigatran. RESULTS:GLP-1RA-induced gastric emptying delays led to increased area under the concentration-time curve (AUC) and prolonged time to maximum concentration (Tmax) for several medications. The model outputs for rosuvastatin, valsartan, and dabigatran indicate increases in AUC by 64%, 90%, and 205%, respectively. Dabigatran, a narrow therapeutic index anticoagulant, exhibited the most significant changes, raising potential concerns of higher drug exposure. CONCLUSIONS:PBPK modeling suggests that GLP-1RAs can influence the pharmacokinetics of oral medications by delaying gastric emptying, potentially leading to clinically relevant DDIs. While further clinical validation and pharmacovigilance is needed, these findings highlight the importance of PBPK tools in predicting and potentially mitigating risks associated with GLP-1RA use.

Accurate kidney function estimation hinges on essential markers of age and body size. The relative benefit of both markers has been debated with the emerging biological age and novel body size descriptors. We used radiomic biomarkers of age-related changes in body composition to construct new biological age indices as covariates of kidney function. A retrospective cohort of hospitalized patients with plasma concentrations of aminoglycosides and computed tomography images were evaluated. Aminoglycoside clearance served as a kidney function surrogate. A population pharmacokinetic model was constructed to determine whether biological age indices improved aminoglycoside clearance estimation compared to chronological age. The final dataset included 156 patients (51.92% female) with a median (minimum-maximum) age and body weight of 58 [21, 93] years and 81 [43.8, 139.3] Kg. A 1-compartment clearance model with linear elimination, incorporating biological index, serum creatinine, and drug type best fits the concentration-time data. The best radiomic biological age model included dorsal muscle group area, bone mineral density, visceral fat area, and subcutaneous fat density. The radiomic biological age model offered a modest improvement over the chronological age model. This work offers a proof-of-concept, highlighting the potential for more precise methods for aging-related kidney function estimation to aid personalized pharmacotherapy.

Accurate kidney function assessment supports healthcare and clinical decision‐making in practice and drug development. Measured glomerular filtration rate (mGFR) via iohexol clearance is the gold standard, but cost, supply issues, and logistical challenges limit its clinical use. Iopamidol, another iodinated contrast agent widely used in CT imaging, has not been studied in humans for mGFR assessment. This study aims to evaluate the pharmacokinetic interchangeability of iohexol and iopamidol for mGFR assessment and to develop a limited sampling strategy to facilitate clinical implementation. In a parallel‐group, single‐dose pharmacokinetic study, 24 healthy adult volunteers with varying kidney function, as defined by the 2021 CKD‐EPI eGFRcr equation (range: 35‐140 mL/min; median: 72 mL/min), received iohexol and iopamidol. Plasma concentrations were measured using liquid chromatography‐mass spectrometry, and population pharmacokinetic modeling estimated drug clearance. Clearance estimates for both agents showed strong agreement (R 2 = 0.82, p < .005), with Bland–Altman analysis indicating minimal bias (mean difference: 15.69 mL/min; LoA: −3.76 to 35.15). A limited sampling strategy using one (1‐h, R 2 = 0.91) or two (1 and 5 h, R 2 = 0.92) time points yielded accurate clearance estimates. These findings suggest that iopamidol may be a viable alternative to iohexol for mGFR determination. Broader access to accurate kidney function testing can enhance drug dosing, reduce misclassification, and improve care for patients with chronic kidney disease. Further research should validate these findings in larger, more diverse populations, including those with advanced kidney impairment.

Obesity can cause physiological changes resulting in antibiotic pharmacokinetic alterations and suboptimal drug exposures. This systematic review aimed to summarise the available evidence on this topic and provide guidance for dose adjustment of antibiotics in adult (age ≥18 years) patients with obesity (BMI >30 kg/m2). We searched PubMed, Embase, and CENTRAL databases to find relevant studies published between database inception and Dec 30, 2023. We initially identified 6113 studies, which became 4654 studies after duplicate removal, and 128 studies were included in the final review. β-lactam antibiotics were most commonly studied (57 studies), followed by the group of glycopeptides, lipoglycopeptides, and oxazolidinones (45 studies). The certainty of evidence was low or very low for all antibiotics and a meta-analysis was not possible due to the heterogeneity of study populations and methods. Obesity modestly alters the pharmacokinetics of β-lactam antibiotics, but evidence does not support routine dose adjustments. For aminoglycosides and glycopeptides, the impact of obesity on pharmacokinetics is evident and weight-based dosing is recommended. Data are sparse for other antibiotic classes and research needs are described. In the absence of robust pharmacokinetic data, therapeutic drug monitoring can be used to guide individualised dosing.

Ceftolozane/tazobactam is a key antibiotic for Pseudomonas aeruginosa infections. Our objective was to determine whether continuous infusion (CI) of ceftolozane/tazobactam can achieve aggressive pharmacokinetic/pharmacodynamic (PK/PD) targets that suppress resistance and improve outcomes in severe Pseudomonas aeruginosa infections. A retrospective analysis of adult patients receiving CI ceftolozane/tazobactam and therapeutic drug monitoring (TDM) of both compounds was performed. Population PK/PD modeling identified the most accurate method for estimating ceftolozane/tazobactam clearance based on kidney function and Monte Carlo simulations investigated the relationship between various CI dosing regimens and aggressive PK/PD target attainment of ceftolozane/tazobactam. The 2021 non-race-based Chronic Kidney Disease Epidemiological Collaboration (CKD-EPI) equation with body surface area indexation provided the most reliable clearance estimates. Simulations showed that CI regimens of 4-6 g/2-3 g daily achieved optimal target attainment (≥90%) across all kidney function strata for MICs up to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint. Cumulative fraction of responses remained robust against key resistance phenotypes: MDR (12.6%; 83.8%), pan-beta-lactam-nonsusceptible (8.2%; 78.2%), and difficult-to-treat resistant (6.7%; 71.7%). Even among isolates with MIC >4 mg/L, aggressive target attainment was reached in 15%-40% of cases. This study suggests that CI ceftolozane/tazobactam, informed by TDM and optimized for aggressive PK/PD targets, offers a promising strategy to maximize efficacy and suppress resistance in severe Pseudomonas aeruginosa infections. These findings warrant prospective clinical trials of CI-based, exposure-guided therapy.

Obesity significantly influences drug pharmacokinetics (PK), which challenges optimal dosing. This study examines the effects of diet-and-exercise-induced weight loss on key drug-metabolizing enzymes and gastric emptying in patients with obesity, who frequently require medications for comorbidities. Participants followed a structured weight management program promoting weight loss over 3-6 months and were not concomitantly on potential CYP inducers or inhibitors. Using a drug cocktail of acetaminophen, caffeine, omeprazole, and midazolam, we assessed UGT1A1, CYP1A2, CYP2C19, and CYP3A4 enzyme activities before and after weight loss, respectively, by measuring parent and metabolite concentrations. The time to maximum acetaminophen plasma concentrations reflected the gastric emptying time. PK profiles were compared across two phases: baseline (Phase 1) and post-weight loss (Phase 2). Twenty-four participants enrolled, 21 completed Phase 1 and 12 completed both phases. Statistically significant (N = 12, P < .05) gains in CYP2C19 and CYP3A4 activity were observed after weight loss of 7.6% to 26.2%, with a median [25th, 75th percentile] increase in activity of 90.5 [15.0, 194.3] % and 43.0 [7.5, 68.0] %, respectively. A 2- or 3-h single plasma sample-based ratio of the metabolite to parent concentration strongly correlated with the respective AUC ratio for the drug metabolism phenotype (N = 21). Our findings provide provisional data for evaluation of the effects of non-pharmacologically and non-surgically induced weight loss on gastric emptying and drug metabolism for future physiologically based PK models. Development of mechanistic models to optimize drug dosing in obesity are necessary since weight and body composition shifts are expected with emerging new treatments.

BACKGROUND:Daptomycin is a high-use intravenous antimicrobial agent affording the convenience of once-daily dosing. Prior studies suggest an opportunity to use a more operationally convenient fixed rather than weight-based dosing but this approach has not been studied prospectively. METHODS:This study quantified the probability of toxicity and efficacy end points by prospectively testing a fixed dose regimen of daptomycin (750 mg) in obese and non-obese adults. At least, three daptomycin concentrations were measured at steady-state for each patient. A population pharmacokinetic model was constructed to evaluate concentration-time profiles and investigate covariates of daptomycin clearance. Simulations were performed to evaluate the probability of achieving efficacy (24-h area under the curve (AUC0-24) ≥ 666 mg∙h/L) and toxicity (minimum concentration (C min) ≥24.3 mg/L) targets for fixed (500-1000 mg) and weight-based (6-12 mg/kg) daptomycin doses. RESULTS:Thirty-one patients (16 females, 15 males) with median (interquartile range (IQR)) age of 50 (30, 62) years and weight of 74 (54, 156) kg were included in the final analysis. Fixed dose daptomycin (750 mg) resulted in similar exposure across weights with a median (IQR) AUC0-24 of 819 (499, 1501) mg∙h/L and 749 (606, 1265) mg∙h/L in patients weighing ≤74 kg and >74 kg, respectively. Overall, male sex and increased kidney function necessitate higher fixed and weight-based doses to achieve efficacy. Creatine phosphokinase elevation was observed in two patients (6.5%) and predicted to be lower with fixed versus weight-based regimens. CONCLUSIONS:Fixed daptomycin dosing adjusted for sex and kidney function is expected to improve the efficacy-to-toxicity ratio, transitions of care, and costs compared to weight-based doses. However, no empiric dosing approach is predicted to achieve ≥90% efficacy while minimizing the risk of toxicity, so therapeutic drug monitoring should be considered on a patient-specific basis.

Background IV fosfomycin is used against MDR Gram-negative bacilli (GNB) but has dose-limiting side effects, especially in patients with impaired kidney function.Objectives To determine the optimal dosage of IV fosfomycin for patients with varying degrees of kidney function.Methods Adult patients receiving IV fosfomycin for treatment of GNB were eligible. Five serial blood samples were collected after at least three doses of fosfomycin; plasma was assayed by LC-MS/MS and modelled by population pharmacokinetic analysis. The PTA for AUC24/MIC of 98.9 for Escherichia coli and Klebsiella pneumoniae, and 40.8 for Pseudomonas aeruginosa were computed by Monte Carlo simulations. Cumulative fractions of response (CFR) were analysed for each pathogen using EUCAST MIC distributions.Results A total of 24 patients were included. Creatinine clearance (CLCR) and gender significantly influenced fosfomycin clearance. The kidney function-adjusted dosing regimens are proposed by using the lowest dose that can achieve >= 90% PTA for AUC24/MIC of 98.9 at an MIC of <= 32 mg/L (EUCAST v.13 susceptibility breakpoint for Enterobacterales). For patients with normal kidney function (CLCR 91-120 mL/min), a dosage of 15 g/day is suggested. This regimen achieved 97.1% CFR against E. coli, whereas CFR was 72.9% for K. pneumoniae and 76.7% for P. aeruginosa.Conclusions A fosfomycin dosage of 15 g/day with adjustment according to kidney function provided high PTA and CFR when treating E. coli. This dosage is lower than that used in current practice and may improve tolerability. Higher dosages may be needed for P. aeruginosa; however, safety data are limited.