Antimicrobial Agents and Chemotherapy最新文献

{"title":"Population pharmacokinetics of piperacillin based on multicenter data to support model-informed precision dosing in critically ill women.","authors":"Sebastian Greppmair, Sina Pesthy, Michael Zoller, Christina Scharf, Alexander Brinkmann, Otto Frey, Johannes Zander, Nadine Liebchen, Stefan Hagel, Sebastian G Wicha, Christoph Dorn, Sabrina Böing, Uwe Liebchen","doi":"10.1128/aac.00986-26","DOIUrl":"https://doi.org/10.1128/aac.00986-26","url":null,"abstract":"<p><p>Sex-specific differences in pharmacokinetics are increasingly recognized as clinically relevant, yet most population pharmacokinetic models for antibiotics have been developed in predominantly male populations with limited transferability to female patients. This study aimed to develop and externally evaluate a population pharmacokinetic model of piperacillin specifically for critically ill women to support model-informed precision dosing (MIPD). A total of 923 samples from 165 critically ill women (from four previously published studies) receiving piperacillin/tazobactam were analyzed. The data set was randomly split into a training set (80%) and an independent external evaluation set (20%). Non-linear mixed-effects modeling was employed based on the training data using NONMEM, and covariates were identified using stepwise covariate modeling with cross-validation. Prediction accuracy and bias were quantified using the median prediction error (MDPE) and the median absolute prediction error (MDAPE) in an MIPD scenario. Model predictions for future concentrations were generated both <i>a priori</i> and through Bayesian forecasting based on one prior sample. A two-compartment model provided the best fit for the data. Clearance was significantly affected by renal function estimated by the Cockcroft-Gault equation, along with procalcitonin and serum albumin. The external evaluation demonstrated strong predictive performance with very low systematic bias. In the MIPD scenario, <i>a priori</i> predictions exhibited good predictive performance (MDPE < |5.2|%, MDAPE < 33.4%), which substantially improved with Bayesian forecasting (MDPE < |3.2|%, MDAPE < 19.1%). A female-specific population pharmacokinetic model of piperacillin was developed and externally validated, demonstrating robust predictive performance and clear benefits for Bayesian forecasting.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0098626"},"PeriodicalIF":4.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A machine learning framework for precision dosing of daptomycin across diverse disease states.","authors":"Xin-Fang Zhang, Jing Sun, Guo-Xiang Hao, Xiao-Mei Chen, Yue Zhou, Xiao-Jie Wang, John van den Anker, Wei Zhao, De-Qing Sun, Bo-Hao Tang","doi":"10.1128/aac.01089-26","DOIUrl":"https://doi.org/10.1128/aac.01089-26","url":null,"abstract":"<p><p>The large pharmacokinetic variability of daptomycin across disease states poses a challenge for individualized dosing. Conventional population pharmacokinetic (PopPK) models are often limited to specific conditions, lacking generalizability. This study used a machine learning (ML) framework to predict daptomycin exposure and guide dose optimization across heterogeneous populations. Nine published PopPK models were used to generate 90,000 simulated profiles across patients with infections and/or patients treated with renal transplantation and/or renal replacement therapy. Seven ML algorithms were trained to predict the 24 h area under the concentration-time curve (AUC_0-24). Model performance was evaluated using statistical metrics and clinical scenario assessments, and comparison with PopPK models. External validation was conducted with real-world data. CatBoost demonstrated the highest predictive accuracy, identifying dose, creatinine clearance, disease state, and weight as key predictors. The validation cohort comprised 20 patients with infections (501 concentration measurements) and 19 patients receiving renal replacement therapy (513 concentration measurements). In infected patients, the prediction error of AUC_0-24 was reduced by 60.1% compared with existing PopPK models (root mean square error [RMSE], 141 vs 353 mg·h/L; mean absolute prediction error, 23.5% vs 58.1%). The ML model correctly classified 75.0% of patients into the appropriate clinical AUC categories (<666, 666-939, and >939 mg·h/L), outperforming PopPK models (average overall accuracy: 30.0%). In patients undergoing renal replacement therapy, ML also improved performance (RMSE, 197 vs 218 mg·h/L; overall accuracy, 52.6% vs 31.6%). The ML model demonstrated accurate prediction of steady-state daptomycin AUC in heterogeneous clinical populations and was successfully validated using real-world data. By enabling accurate pre-treatment exposure prediction, it provides a flexible and clinically useful pathway toward precision dosing of daptomycin.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0108926"},"PeriodicalIF":4.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic/pharmacodynamic evaluation of multidose oritavancin for prolonged durations of therapy.","authors":"Cecilia F Volk, Max Blumenthal, Nolan Thomas, Wesley D Kufel, Warren E Rose, Sin Yin Lim","doi":"10.1128/aac.01049-26","DOIUrl":"https://doi.org/10.1128/aac.01049-26","url":null,"abstract":"<p><p>Managing multidrug-resistant gram-positive infections is challenging, especially when prolonged therapy is needed for conditions like bacteremia, endocarditis, osteomyelitis, or other deep-seated infections. Oritavancin, a long-acting lipoglycopeptide, is increasingly used in these scenarios and offers an alternative to central catheter placement. However, despite its growing use for extended treatment, optimal dosing strategies and pharmacokinetic targets remain unclear. An <i>in silico</i> pharmacokinetic/pharmacodynamic simulation was performed to assess the predicted oritavancin concentration resulting from weekly and every 2-week dosing regimens. The simulations utilized a previously published model, which utilized pharmacokinetic sampling data from two single-dose, phase 3 clinical trials. A 100% free time above the MIC was utilized as the pharmacodynamic target. The Clinical and Laboratory Standards Institute breakpoint (0.12 µg/mL) and MIC90 (0.06 µg/mL) values for both <i>Staphylococcus aureus</i> and <i>Enterococcus faecalis</i> were utilized as benchmarks. Eighty-five percent protein binding was assumed. A six-dose regimen of 1,200 mg weekly is expected to maintain free plasma concentrations above the breakpoint for a median of 10.4 weeks (lower 5th percentile 9.6) and above the MIC90 for about 1.5 weeks longer, exceeding what is usually required for acute treatment of most infections. Alternatively, using a three-dose regimen of 1,200 mg every 2 weeks is expected to maintain free plasma concentrations above the breakpoint for a median of 8.4 weeks (lower 5th percentile 7.9), with trough values remaining therapeutic between doses. Every 2-week dosing strategies are expected to maintain therapeutic concentrations between doses. This strategy may be employed to reduce the cost of treatment and improve patient convenience.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0104926"},"PeriodicalIF":4.2,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efflux reprogramming promotes <i>Staphylococcus aureus</i> persistence with <i>Pseudomonas aeruginosa</i> in cystic fibrosis.","authors":"Q C Truong-Bolduc, Y Wang, B Alvarez-Carcamo, C Steifman, B G Lawton, L M Yonker, B P Hurley, L G Rahme, D C Hooper","doi":"10.1128/aac.01070-26","DOIUrl":"https://doi.org/10.1128/aac.01070-26","url":null,"abstract":"<p><p><i>Staphylococcus aureus</i> persists in cystic fibrosis (CF) airways despite <i>in vitro</i> antibiotic susceptibility, suggesting that efflux reprogramming driven by environmental and polymicrobial interactions with <i>Pseudomonas aeruginosa</i> promotes survival in this setting. In this study, we investigated how CF-like conditions and co-infection with <i>P. aeruginosa</i> influence <i>S. aureus</i> physiology and antimicrobial response. Using artificial sputum medium (ASM) and co-culture models, we found that ASM induced a selective transcriptional response characterized by upregulation of the multidrug efflux pump <i>tet38</i>, while other pumps remained minimally expressed. In the presence of <i>P. aeruginosa</i>, <i>S. aureus</i> maintained <i>tet38</i> expression but additionally induced <i>norB</i>, indicating a redistribution of efflux activity under polymicrobial stress. <i>P. aeruginosa</i> metabolites, including quinolines and phenazines, contributed to this response, and deletion of <i>tet38</i> or <i>norB</i> significantly reduced <i>S. aureus</i> fitness in ASM and co-culture conditions. Analysis of <i>S. aureus</i> clinical isolates from people with CF revealed a similar hierarchy, with Tet38 and NorB as the predominant efflux pumps, particularly in <i>S. aureus</i> isolates co-recovered with <i>P. aeruginosa</i>. Despite exhibiting only low-level increases in MICs, these isolates demonstrated enhanced survival in ASM. Notably, <i>S. aureus</i> isolates paired with clinical <i>P. aeruginosa</i> strains showed improved survival compared with survival when paired with a <i>P. aeruginosa</i> reference strain, consistent with adaptation toward coexistence. Together, these findings demonstrate that CF-like environmental conditions and polymicrobial interactions drive selective reprogramming of efflux pumps that promote <i>S. aureus</i> persistence without conferring high-level resistance, highlighting a mechanism of antibiotic tolerance not captured by standard susceptibility testing.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0107026"},"PeriodicalIF":4.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Open-label Phase 1 study to evaluate drug-drug interactions between ulonivirine and islatravir in adults without HIV.","authors":"Jesse C Nussbaum, Michelle M Pham, Ryan Vargo, Yang Liu, Ilias Triantafyllou, Natasha Boyette, Randolph P Matthews, Marian Iwamoto, Gillian Gillespie","doi":"10.1128/aac.00676-26","DOIUrl":"https://doi.org/10.1128/aac.00676-26","url":null,"abstract":"<p><p>Ulonivirine is a non-nucleoside reverse transcriptase inhibitor in clinical development for once-weekly oral treatment of HIV-1 in combination with islatravir. This open-label, 3-period, Phase 1 study (MK-8507-016, NCT06619678) in adults without HIV evaluated the potential drug-drug interactions (DDIs) between ulonivirine and islatravir. In Period 1, participants received islatravir 2 mg on Day 1. In Period 2, participants received ulonivirine 200 mg on Days 1 and 8. In Period 3, a single dose of islatravir 2 mg was co-administered with ulonivirine 200 mg 7 days after the Day 8 dose in Period 2, followed by four doses of ulonivirine 200 mg once weekly. Thirty-six participants (58% female, 67% White, median age 43 years) were enrolled. Plasma pharmacokinetics of islatravir and ulonivirine were similar with and without coadministration. The 90% <i>CIs</i> for geometric mean ratios of co-administration versus single administration of islatravir (AUC_0-168, 1.06 [1.02-1.09]; C₁₆₈, 1.05 [0.98-1.12]; C_max, 1.10 [1.02-1.19]) and ulonivirine (AUC_0-168, 1.07 [1.05-1.09]; C₁₆₈, 1.08 [1.04-1.12]; C_max, 1.03 [0.98-1.07]) were within standard bioequivalence bounds (0.8-1.25). During Period 3 (co-administration with ulonivirine), intracellular ISL-triphosphate AUC_0-168, AUC_0-inf, C_max, and C₁₆₈ were approximately 21%, 15%, 16%, and 10% lower, respectively, compared with ISL alone. These differences may in part reflect variability in peripheral blood mononuclear cell counts. Adverse events, laboratory test results, and other safety parameters were comparable among all three periods. In conclusion, no clinically meaningful DDIs were observed between ulonivirine 200 mg and islatravir 2 mg, supporting continued development of this combination for HIV-1 treatment.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0067626"},"PeriodicalIF":4.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population pharmacokinetics modeling of albendazole and its active metabolite, albendazole sulfoxide in mass drug administration against lymphatic filariasis.","authors":"Abdullah Alshehri, Christopher L King, Daryl J Murry","doi":"10.1128/aac.00562-26","DOIUrl":"https://doi.org/10.1128/aac.00562-26","url":null,"abstract":"<p><p>Albendazole (ALB), a benzimidazole antiparasitic, is widely used in mass drug administration (MDA) campaigns against lymphatic filariasis (LF). It is rapidly metabolized to its active form, albendazole sulfoxide (ALB-OX), which exhibits considerable interindividual variability (IIV) in pharmacokinetics (PK). This variation may affect ALB efficacy in MDA programs. We developed a population pharmacokinetic (PopPK) model characterizing ALB and ALB-OX exposure and identifying demographic and clinical covariates contributing to IIV in patients with LF and healthy individuals. Plasma concentration-time data were pooled from three clinical studies involving ALB co-administered with ivermectin and diethylcarbamazine. Nonlinear mixed-effects modeling was conducted using Phoenix NLME. Covariate effects (e.g., sex, age, infection status) were assessed, and model validation employed visual predictive checks and bootstrapping. Simulations explored covariate impact on exposure. A joint two-compartment model with transit absorption for ALB and pre-systemic ALB-OX formation best described the data. Sex significantly influenced ALB-OX clearance and volume of distribution, with males exhibiting higher clearance and lower exposure. Body weight, age, and LF infection status did not significantly affect PK parameters. Simulations confirmed 33% lower ALB-OX levels in males compared to females following a 400 mg oral ALB dose. This is the first PopPK model of ALB and ALB-OX in LF-endemic populations. It highlights sex as a key covariate explaining IIV in ALB-OX exposure, with implications for optimized dosing in MDA programs. Further studies incorporating pharmacogenetics and pediatric data are warranted.This study is registered with ClinicalTrials.gov as NCT04410406, NCT02845713, and NCT03664063.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0056226"},"PeriodicalIF":4.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A gene network regulating echinocandin heteroresistance in <i>Candida glabrata</i>.","authors":"Abigail A Harrington, Kyle W Cunningham","doi":"10.1128/aac.00549-26","DOIUrl":"10.1128/aac.00549-26","url":null,"abstract":"<p><p>While pathogenic fungi can acquire resistance to the current arsenal of antifungals through genetic mutations, heteroresistance has emerged as an important new cause of therapeutic failures. Heteroresistance is generally thought to arise in small subpopulations that display phenotypic resistance to antifungals without genetic mutations. This study blurs that line by showing gain-of-resistance (GOR) mutations in <i>FKS2</i>, which encodes a target of echinocandins and fungerps, causing broad heteroresistance in <i>Candida glabrata</i>. Identical gain-of-resistance mutations in <i>FKS1</i>, a paralog of <i>FKS2</i>, caused resistance and little or no heteroresistance. Heteroresistance of <i>FKS2-GOR</i> strains decreased when stress-responsive transcription factors (Crz1 and Rlm1) known to increase <i>FKS2</i> expression were eliminated and was nearly abolished when the upstream regulators (calcineurin and Slt2) were mutated or inhibited. Conversely, stresses and mutations known to increase <i>FKS2</i> expression also increased the survival of <i>FKS2-GOR</i> mutants exposed to high doses of echinocandins. A genome-wide screen using transposon sequencing revealed additional regulators of heteroresistance and resistance. Mutants lacking <i>DFG5</i> or <i>SSK2</i> exhibited strongly increased <i>FKS2-GOR</i> function without increased expression. Mutants lacking <i>IRA1</i>, an inhibitor of the Ras1-PKA signaling pathway that senses glucose availability, decreased expression of <i>FKS2</i> and increased expression of <i>FKS1</i>, thereby decreasing heteroresistance and increasing resistance, respectively, when these genes carried GOR mutations. The findings suggest that heterogeneous expression of resistance genes and heterogeneous regulation of their products combine to produce echinocandin heteroresistance. Analogous mechanisms may facilitate heteroresistance to azoles and echinocandins in other <i>Candida</i> species.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0054926"},"PeriodicalIF":4.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling the potential effect of cabamiquine-pyronaridine for chemoprevention against <i>Plasmodium falciparum</i> malaria.","authors":"Lucy C Okell, Perrine Courlet, Filippo Venezia, Claude Oeuvray, Claudia Demarta, Thomas Spangenberg, Joseph Okebe","doi":"10.1128/aac.00434-26","DOIUrl":"https://doi.org/10.1128/aac.00434-26","url":null,"abstract":"<p><p>Preventive treatment (chemoprevention) is a key intervention for reducing the burden of <i>Plasmodium falciparum</i> malaria in children. The impact of the current widely used drug combination, sulfadoxine-pyrimethamine-amodiaquine (SP-AQ), is challenged by emerging drug resistance and adherence to multi-day dosing. Cabamiquine is a novel antimalarial with activity against liver- and blood-stage malaria parasites, administered as a single dose, and under development in combination with pyronaridine. We used mathematical modeling to translate early phase 1 clinical results into estimates of its potential impact as malaria chemoprevention. Pharmacokinetic-pharmacodynamic (PKPD) models of cabamiquine and pyronaridine were combined, assuming Bliss independence, to estimate time-varying protection against infection. PKPD results were incorporated into an established individual-based malaria transmission model to estimate the impact of seasonal malaria chemoprevention (SMC) across settings with differing transmission and seasonality. Cabamiquine-pyronaridine was predicted to provide protection of >95% for approximately 4 weeks, slightly outperforming SP-AQ even in children who fully adhere to SP-AQ treatment. Six weeks after treatment, cabamiquine-pyronaridine protection dropped for the regimens containing <200 mg cabamiquine, but the combination could still outperform SP-AQ at doses ≥200 mg. If deployed as SMC, a longer duration of protection may enable fewer, more widely spaced treatment cycles while maintaining impact, improving projected cost-effectiveness. Cabamiquine-pyronaridine shows strong potential as a next-generation single-dose chemoprevention regimen, supporting continued clinical development and evaluation.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0043426"},"PeriodicalIF":4.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>In vitro</i> in-depth characterization of emodepside in combination with key anthelmintic drugs on soil-transmitted helminths.","authors":"Anastasia Schärer, Cécile Häberli, Dominique Schlienger, Jennifer Keiser","doi":"10.1128/aac.00825-26","DOIUrl":"https://doi.org/10.1128/aac.00825-26","url":null,"abstract":"<p><p>Despite the enormous disease burden, treatments are limited for soil-transmitted helminthiasis. The handful of anthelmintic drugs suffer from variable and often insufficient efficacy against the pathogens. Resistance development, caused by high drug pressure, is an ongoing concern. New treatments are needed, and combination therapies may represent a promising therapeutic strategy. We explored emodepside as a partner in combination therapy and characterized drug-interaction effects with key anthelmintics <i>in vitro</i> against different soil-transmitted helminths (STHs). Drug-interaction studies were carried out in human recombinant cytochromes P450 assays. Combination studies revealed species-, stage-, and drug-dependent interaction profiles. For benzimidazole-emodepside combinations, potentiation was only observed against <i>Ancylostoma ceylanicum</i> larvae, while against adult stages, up to threefold potentiation or synergy (ΣFIC < 0.9) was observed for <i>Heligmosomoides polygyrus</i> and <i>Trichuris muris</i>, especially for albendazole and albendazole sulfoxide. Combinations of emodepside with macrocyclic lactones showed mostly strong synergy against <i>H. polygyrus</i> larvae (ΣFIC 0.06-2.52), while other species trended toward antagonism (ΣFIC >1.5). Against adult stages, potentiation or synergism was observed in <i>H. polygyrus</i> and <i>T. muris</i>, while against <i>Strongyloides ratti</i>, only the moxidectin-emodepside combination was synergistic (ΣFIC 0.69-0.99). For nAChR agonists, levamisole showed the strongest effect against <i>Necator americanus</i> larvae, while oxantel pamoate exhibited potentiation or synergistic effects across multiple species and life stages. CYP450 inhibition assays reveal no relevant drug-drug interactions. This study provides a thorough evaluation of emodepside as a combination partner against soil-transmitted helminths <i>in vitro</i>, paving the way for <i>in vivo</i> studies and ultimately a novel combination therapy with emodepside against STH infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0082526"},"PeriodicalIF":4.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and validation of a cefepime population pharmacokinetic model to guide treatment for patients with hospital-acquired pneumonia requiring renal replacement.","authors":"Adrian Valadez, Emma Harlan, Marc H Scheetz, Michael N Neely, Helen K Donnelly, Richard G Wunderink, Nathaniel J Rhodes","doi":"10.1128/aac.00900-26","DOIUrl":"https://doi.org/10.1128/aac.00900-26","url":null,"abstract":"<p><p>Cefepime is used in critically ill pneumonia patients, but dosing in renal replacement therapy (RRT) is complicated by altered renal function, extracorporeal removal, and variability in pulmonary epithelial lining fluid (ELF) exposure. We sought to develop an integrated model linking systemic, extracorporeal, and pulmonary cefepime pharmacokinetics in RRT. Pharmacokinetic (PK) data from critically ill adults receiving cefepime and requiring RRT were included. In a dedicated continuous RRT (CRRT) cohort (<i>n</i> = 8), pre- and post-filter plasma and effluent PK data were collected. Additional patients (<i>n</i> = 43) requiring RRT also contributed plasma and ELF samples. A non-parametric population PK model was developed using an 80/20 subject-level development-validation split. Covariate models assessed the impact of residual renal function, effluent flow rate, body size, and fixed intradialytic hemodialysis (HD) clearance. Monte Carlo simulations evaluated plasma and ELF target attainment across dosing strategies, weight strata, and minimum inhibitory concentrations (MICs). The final model jointly described systemic, extracorporeal, and pulmonary cefepime disposition using piecewise central volume, native clearance, linear effluent-flow-dependent CRRT clearance, fixed HD clearance, and ELF distribution. Simulations showed adequate plasma target attainment, whereas ELF attainment was sensitive to MIC, target, regimen, and body weight. Continuous infusions of 4 g/day provided adequate ELF attainment at MICs ≤4 mg/L. Plasma-based cefepime target attainment may overestimate pulmonary exposure during RRT, particularly at higher MICs, body weights, and <i>f</i>T>MIC targets. External validation and prospective studies are needed to refine pulmonary target estimates and determine whether plasma-guided Bayesian dosing can reliably ensure site-of-infection exposure.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0090026"},"PeriodicalIF":4.2,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149134989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}