Journal of Antimicrobial Chemotherapy最新文献

{"title":"Mutation-driven alterations in the AcrB efflux pump modulate antibiotic resistance in Klebsiella pneumoniae.","authors":"Roy Dinata, Piyush Baindara, Sourav Chakraborty, Safikureshi Mondal, Santi M Mandal","doi":"10.1093/jac/dkag270","DOIUrl":"https://doi.org/10.1093/jac/dkag270","url":null,"abstract":"<p><strong>Objectives: </strong>To investigate the global prevalence of the acrB efflux transporter among antibiotic resistance genes (ARGs) in Klebsiella pneumoniae and to determine how mutations within AcrB drug-binding pockets influence structural stability and antibiotic interactions.</p><p><strong>Methods: </strong>A global genomic analysis of 42 ARGs reported in K. pneumoniae isolates worldwide was performed to identify the prominence of acrB. A total of 92 AcrB protein sequences were assessed for drug-binding pocket mutations relative to the wild-type strain NCTC9637. De novo protein structures were generated using AlphaFold2 and evaluated through molecular dynamics (MD) simulations. MD analyses were conducted with multiple antibiotics to assess the impact of pocket mutations on drug-binding affinities.</p><p><strong>Results: </strong>acrB emerged as the most widely distributed ARG, conferring resistance to at least 12 antibiotic classes. Three isolates, NCTC9617, NCTC9645, and NCTC13635, displayed multiple drug-binding pocket mutations when compared with the wild type. MD simulations revealed marked structural instability in NCTC9645, while NCTC13635 showed convergence towards a wild-type-like conformation. Docking analyses demonstrated that binding pocket mutations altered antibiotic-binding affinities, suggesting possible alterations in substrate recognition and transport.</p><p><strong>Conclusions: </strong>AcrB is a key driver of multidrug resistance in K. pneumoniae, and mutations within its drug-binding pockets can significantly impact protein stability and antibiotic-binding behaviour. Monitoring these structural variations may help predict emerging resistance patterns and guide therapeutic decision-making.</p><p><strong>Importance: </strong>Multidrug-resistant Klebsiella pneumoniae infections are a growing clinical threat with limited therapeutic options. By integrating global resistance gene surveillance with structural modelling of AcrB efflux pump variants, this study identifies drug-binding pocket mutations that modulate antibiotic affinity and efflux pump stability. These insights provide a molecular basis for predicting treatment failure, guiding precision antibiotic therapy, and advancing the development of efflux pump inhibitors as adjunctive treatments for drug-resistant Gram-negative infections.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 9","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148673835","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":"Treatment of acyclovir-resistant varicella-zoster virus keratitis with amenamevir in an immunocompromised patient.","authors":"Antoine Portais, Stéphane Lastere, David Boutolleau","doi":"10.1093/jac/dkag275","DOIUrl":"https://doi.org/10.1093/jac/dkag275","url":null,"abstract":"","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 9","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148678368","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":"Inter- and intraindividual variability of long-acting injectable cabotegravir/rilpivirine trough concentrations after 1 year of continuous use.","authors":"Shawnalyn W Sunagawa, Joshua P Havens, Sara H Bares, Maureen Kubat, Jennifer O'Neill, Elizabeth Lyden, Timothy Mykris, Lee C Winchester, Jonathan Weinhold, Sean N Avedissian, Anthony T Podany, Courtney V Fletcher, Kimberly K Scarsi","doi":"10.1093/jac/dkag282","DOIUrl":"https://doi.org/10.1093/jac/dkag282","url":null,"abstract":"<p><strong>Objectives: </strong>Long-acting injectable (LAI) cabotegravir/rilpivirine demonstrates substantial inter- and intraindividual variability in trough concentrations during the first year of use. We aimed to characterize trough concentration variability of cabotegravir and rilpivirine after >12 months of continuous use.</p><p><strong>Methods: </strong>We conducted a prospective pharmacokinetic study in virologically suppressed people with HIV receiving bimonthly LAI cabotegravir/rilpivirine 600 mg/900 mg. Plasma trough samples were collected prior to three consecutive doses over 6 months for drug quantitation. Primary outcomes were inter- and intraindividual variability defined as coefficient of variation (CV) and intraclass correlation coefficient (ICC). Secondary outcomes included concentrations below the proposed 4x-protein-adjusted 90% inhibitory concentration (PA-IC90) for cabotegravir (4x-PA-IC90 = 664 ng/mL) and rilpivirine (4x-PA-IC90 = 48 ng/mL).</p><p><strong>Results: </strong>Among 50 participants, 150 samples were collected. Participants were primarily male (80%) with a median age of 45 years and a body mass index of 28 kg/m2. Median interindividual CVs were high for both cabotegravir [58%, interquartile range (IQR): 15, 59] and rilpivirine (52%, IQR: 18, 59). Median intraindividual CVs were moderate for both cabotegravir (24%, IQR: 15, 39) and rilpivirine (23%, IQR: 15, 39), with ICCs indicating good intraindividual agreement for cabotegravir (0.82) and moderate intraindividual agreement for rilpivirine (0.72). Twelve (8%) cabotegravir concentrations in 8 participants and 24 (16%) rilpivirine concentrations in 16 participants were below 4x-PA-IC90; however, all participants maintained virologic suppression throughout the study period.</p><p><strong>Conclusions: </strong>After one year of continuous use, inter- and intraindividual variability persists for cabotegravir and rilpivirine, indicating that clinical decisions should not be based on only one trough concentration.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 9","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706620","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":"Characterization of the intrinsic AmpC β-lactamase of Escherichia marmotae and its impact on decreased susceptibility to cefiderocol and resistance to broad-spectrum cephalosporins.","authors":"Samanta Freire, Sandra Martinez Alvarez, Jacqueline Findlay, Miriam Vogel, Patrice Nordmann, Laurent Poirel","doi":"10.1093/jac/dkag271","DOIUrl":"10.1093/jac/dkag271","url":null,"abstract":"<p><strong>Objectives: </strong>We aimed to characterize the intrinsic AmpC β-lactamase (EMC-2) from an Escherichia marmotae clinical isolate recovered from a bloodstream infection, exhibiting resistance to broad-spectrum cephalosporins.</p><p><strong>Methods: </strong>Cloning experiments in Escherichia coli were performed to evaluate the impact of the respective AmpC enzymes on β-lactam susceptibility. Purification of the enzymes was performed by ion-exchange chromatography, and kinetic assays were performed by UV spectrophotometry.</p><p><strong>Results: </strong>By comparing the sequence of this AmpC with that of a WT E. marmotae, four amino acid substitutions and one amino acid deletion at position 296 were identified. Furthermore, a promoter alteration was responsible for an enhanced gene expression. Production of EMC-2 in E. coli TOP10 conferred an extended-spectrum AmpC (ESAC) phenotype characterized by increased MICs of cefotaxime, cefepime and cefiderocol. Site-directed mutagenesis confirmed the important role of the Arg296 deletion in this phenotype.</p><p><strong>Conclusions: </strong>We showed that the intrinsic AmpC of E. marmotae can acquire both structural and regulatory modifications that broaden its substrate spectrum, leading to reduced susceptibility to clinically relevant β-lactams, including cefiderocol.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 9","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13469691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148724590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antifungal susceptibility profiles of clinical and environmental Scedosporium and Lomentospora isolates from Taiwan: focus on olorofim activity and phylogenetic heterogeneity.","authors":"Shang-Yi Lin, Yi-Ting Tseng, Khaled Abdrabo El-Sayid Abdrabo, Hsin-Mao Wu, Pei-Lun Sun, Chong Kei Lao, Chien-Cheng Lai, Chi-Jung Wu, Passanesh Sukphopetch, Sharon C A Chen, Yin-Tse Huang","doi":"10.1093/jac/dkag236","DOIUrl":"10.1093/jac/dkag236","url":null,"abstract":"<p><strong>Background: </strong>Scedosporium and Lomentospora species are intrinsically resistant moulds increasingly implicated in invasive infections. Olorofim, a novel orotomide antifungal, has demonstrated potent activity against several moulds. This study evaluated the antifungal susceptibility of clinical and environmental isolates, focusing on olorofim, and examined these data in a phylogenetic context.</p><p><strong>Methods: </strong>A total of 216 isolates (Scedosporium spp., n = 205; L. prolificans, n = 11) were collected from clinical and environmental sources across Taiwan. Antifungal susceptibility was determined using the CLSI M38-A3 method. Correlation analyses assessed cross-resistance patterns, while phylogenetic signal, Mantel tests, and variance partitioning were used to evaluate evolutionary structuring of MICs.</p><p><strong>Results: </strong>Scedosporium apiospermum (46.3%) and S. boydii (15.7%) were the predominant species, exhibiting comparable triazole susceptibility profiles (MIC90: voriconazole 1-2 mg/L, posaconazole 4 mg/L, and isavuconazole 8 mg/L). L. prolificans displayed pan-resistance to all agents except olorofim. Olorofim exhibited the lowest MICs across Scedosporium spp. and L. prolificans (all MIC90 ≤ 0.12 mg/L). The isolate source exerted limited biological impact on antifungal susceptibility campared with species-specific characteristics. The association between antifungal susceptibility and species relatedness varied by drug: moderate for posaconazole, amphotericin B, and voriconazole; intermediate for olorofim; weak for isavuconazole; and absent for itraconazole. The majority of MIC variability (72.5%-89.2%) was observed within rather than between species.</p><p><strong>Conclusions: </strong>Susceptibility in Scedosporium and Lomentospora exhibits high intraspecies variability. Triazoles showed only moderate phylogenetic conservation and cross-resistance, whereas olorofim demonstrated potent, independent activity across all taxa. Given the limited predictive value of species identity, individual susceptibility testing remains essential.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 8","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148436585","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":"Systematic review and meta-analysis to identify meropenem exposures and pharmacological targets predictive of clinical outcomes.","authors":"Tim Luxton, Robert West, Natalie King, Richard Gould, Christoph Wälti, Jonathan A T Sandoe","doi":"10.1093/jac/dkag230","DOIUrl":"10.1093/jac/dkag230","url":null,"abstract":"<p><strong>Background: </strong>Meropenem is a broad-spectrum carbapenem reserved for severe infections. Pharmacokinetic variability has been observed in meropenem patients, and its optimal pharmacological target remains unclear. This meta-analysis evaluated meropenem exposure, target attainment, and their association with clinical outcomes to clarify effective pharmacological targets.</p><p><strong>Methods: </strong>Following PRISMA (PROSPERO CRD42024499652), studies were identified that measured meropenem concentrations in patient samples and reported clinical outcomes. Studies were synthesized and predictors for clinical outcomes were identified by meta-analysis. Patient-level data, provided by authors, were analysed by multivariate logistic regression to identify predictors for clinical outcomes.</p><p><strong>Results: </strong>In total, 42 studies were included, comprising 2264 patients. Most studies had a high risk of bias in this context. Pooled clinical cure was 70.0% and 30-day mortality 22.2%. Meropenem concentration was not associated with clinical cure (OR 1.01 per mg/L, 95% CI 0.97-1.05, P = 0.702), whereas attaining 100%ƒT > MIC was marginally associated with cure (OR 1.02 per 1%, 1.00-1.04, P = 0.0552). Higher meropenem exposure was associated with increased 30-day mortality (OR 1.064 per mg/L, 1.008-1.124, P = 0.025). In patient-level analysis (six studies, 295 patients), meropenem exposure, SOFA score and age were each independently associated with mortality.</p><p><strong>Discussion: </strong>Higher meropenem concentrations were associated with increased mortality across both cohort and patient-level analyses, challenging the assumption that universally higher dosing benefits all patients. However, residual confounding by illness severity could not be excluded, thus this finding should be considered hypothesis generating. Attaining 100%ƒT > MIC may improve cure while avoiding excessive concentrations may reduce harm, further research into meropenem personalized dosing is required.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 8","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13364777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148436748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic potential and safety challenges of antimicrobial peptides and peptidomimetics against ESKAPEE pathogens: a systematic review with quantitative analysis.","authors":"Elias Shiferaw Mekonen, Shyam Kumar Mishra, Umme Laila Urmi, Yihenew Million Yeshtila, Furqan A Maulvi, Naresh Kumar, Mark D P Willcox","doi":"10.1093/jac/dkag255","DOIUrl":"10.1093/jac/dkag255","url":null,"abstract":"<p><strong>Background: </strong>Antimicrobial peptides and peptidomimetics have emerged as promising alternatives to traditional antibiotics for MDR bacterial infections. Their advancement, however, is often limited by toxicity and poor pharmacokinetics. In this review, we apply a rigorous quantitative framework to evaluate the therapeutic balance of potency and safety for these agents, offering new perspectives that extend beyond previous descriptive analyses.</p><p><strong>Methods: </strong>We systematically searched key biomedical databases (January 2000 to May 2025) for studies reporting antimicrobial potency, cytotoxicity, selectivity index, stability and in vivo efficacy. Bias was assessed using an adapted laboratory animal experimentation quality tool. Data were synthesized using a pooled geometric mean approach to compare therapeutic windows across compound.</p><p><strong>Results: </strong>Of 136 peptides from 47 studies, natural antimicrobial peptides were most potent in vitro against Gram-negative bacteria but frequently caused significant host toxicity. Limited cytotoxicity data prevented robust selectivity analysis for these natural compounds. Peptidomimetics generally provided a wider safety margin than synthetic peptides, though toxicity was context dependent. Major translational barriers, including protein binding and cation effects, diminished in vivo efficacy. Notably, some rationally designed compounds achieved therapeutic benefit in animal models without acute toxicity, unlike traditional agents such as polymyxin B.</p><p><strong>Conclusions: </strong>Advancing antimicrobial peptides and peptidomimetics into clinical use will require overcoming the fundamental trade-off between potency and safety. Natural compounds remain restricted by toxicity, while synthetic agents and peptidomimetics promise better safety but face pharmacokinetic challenges. Future research should prioritize innovative delivery approaches to enhance efficacy and reduce toxicity, enabling these novel therapies to address MDR infections.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 8","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13403570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148591656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarker-driven strategy for early discontinuation of empirical antifungal treatment in critically ill patients: the role of (1-3)-β-D-glucan using Wako® test.","authors":"M Albanell-Fernández, M Tuset, A Vergara, M Villanueva, M Barrantes-González, M Bodro, A Soriano, M Hernández-Meneses, G Muñoz-Rojas, S Herrera","doi":"10.1093/jac/dkag226","DOIUrl":"10.1093/jac/dkag226","url":null,"abstract":"<p><strong>Background: </strong>(1,3)-β-D-Glucan (BDG) testing with Fungitell® assay has been shown to support antifungal stewardship by shortening empirical antifungal therapy in critically ill patients; however, data on Wako® assay are lacking.</p><p><strong>Methods: </strong>Prospective, non-randomized study conducted over 15 months in a tertiary care hospital. Critically ill patients receiving empirical echinocandin therapy with a BDG measurement within 48 h were included. Patients were stratified by Candida score (low risk <3, high risk ≥3) and initial BDG result and followed for 30 days after discontinuation or death. The primary endpoint was early echinocandin discontinuation and total antifungal duration. Secondary endpoints included mortality, invasive candidiasis (IC) within 30 days, length of stay and antifungal consumption.</p><p><strong>Results: </strong>Ninety patients were included. Among low-risk patients (n = 27), 81.5% (22/27) had negative BDG; antifungal therapy was discontinued early in 77.3% (17/22) of BDG-negative versus 20% (1/5) of BDG-positive cases, with no IC diagnosed. Among high-risk patients (n = 63), 58.7% (37/63) had negative BDG; therapy was discontinued in 75.7% (28/37). In high-risk patients with positive BDG (n = 26), there were 3 IC (11.5%); in all cases, the antifungal was maintained. Early discontinuation was more frequent in BDG-negative patients (77.2% versus 19.2%; P < 0.001), resulting in shorter echinocandin (2 versus 4 days; P = 0.004) and total antifungal therapy (3 versus 8 days;P < 0.001), without differences in mortality or subsequent IC. Echinocandin costs decreased by ∼50%.</p><p><strong>Conclusions: </strong>BDG-guided management using Wako® assay increased early antifungal discontinuation and reduced echinocandin exposure. BDG should be used cautiously as an adjunctive tool, particularly in high-risk patients, due to potential false negatives.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 8","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148584353","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":"External validation of a model informed precision dosing software for cefotaxime for treating critical ill infants and children.","authors":"Quyen Tu, Sainath Raman, Menino Osbert Cotta, Luregn Schlapbach, Tavey Dorofaeff, Andras Farkas, Jason A Roberts","doi":"10.1093/jac/dkag235","DOIUrl":"10.1093/jac/dkag235","url":null,"abstract":"<p><strong>Objectives: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 8","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148591702","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":"Effect of adjunctive inhalation on the association between plasma AUC/MIC of polymyxin B and clinical efficacy in MDR gram-negative infections.","authors":"Shengnan Zhang, Yaqian Li, Hongyi Tan, Yejun Li, Yuanfang Qin, Tingting Wu, Jingjing Liu, Qi Pei","doi":"10.1093/jac/dkag238","DOIUrl":"10.1093/jac/dkag238","url":null,"abstract":"<p><strong>Objectives: </strong>To develop a population pharmacokinetic (PPK) model of polymyxin B for intravenous (IV) and combined intravenous plus inhaled (IV + IH) administration in critically ill patients, and evaluate the association between plasma 24-h steady-state area under concentration-time curve to minimum inhibitory concentration ratio (AUCss,24h/MIC) and clinical outcomes.</p><p><strong>Methods: </strong>In this prospective observational cohort study, adults with multidrug-resistant Gram-negative bacterial infections receiving polymyxin B  ≥ 48 h were enrolled and assigned to IV or IV + IH groups. Plasma samples were analysed by validated HPLC-MS/MS. PPK models were developed with NONMEM. Clinical efficacy at the end of treatment was blindly assessed.</p><p><strong>Results: </strong>Forty-three patients were enrolled (IV, n = 22; IV + IH, n = 21), with an overall clinical success rate of 66.7%. A two-compartment PPK model best described the data. The typical clearance was 2.61 L/h, with creatinine clearance and total bile acids identified as significant covariates. In the overall cohort, no significant differences in AUCss,24h or AUCss,24h/MIC were observed between clinical success and failure (P = 0.591 and 0.143, respectively). In the IV group, AUCss,24h/MIC was significantly higher in responders (P = 0.005), and an ROC analysis suggested an exploratory efficacy threshold of 94.4; AUCss,24h showed a non-significant trend (P = 0.076). No exposure-response relationship was observed in the IV + IH group (P = 0.398 and 0.495, respectively).</p><p><strong>Conclusions: </strong>Plasma AUCss,24h/MIC appears to be associated with clinical efficacy during IV monotherapy but not in IV + IH regimens, possibly due to high pulmonary exposure. Plasma-based PK/PD targets should be applied cautiously when inhalation is added.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 8","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148436721","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}