Antimicrobial Agents and Chemotherapy最新文献

{"title":"Evaluation of omadacycline <i>in vitro</i> activity against <i>Corynebacterium</i> species.","authors":"Saltanat Ualiyeva, Justin McCallum, Alexander Donald Pyden, Zoe Freeman Weiss","doi":"10.1128/aac.01864-24","DOIUrl":"10.1128/aac.01864-24","url":null,"abstract":"<p><p><i>Corynebacterium</i> spp. are gram-positive bacteria increasingly recognized as pathogens. This study evaluates the MICs of omadacycline, a tetracycline, against 40 clinical <i>Corynebacterium</i> isolates using two methodologies: broth microdilution (BMD) and Liofilchem omadacycline MIC Test Strip (MTS). By BMD, the MIC₅₀, MIC₉₀, and MIC range were 0.5 µg/mL, 1 µg/mL, and 0.12-2.0 µg/mL, respectively. Comparing BMD to MTS, essential agreement (EA, within ±1 doubling dilution of the reference BMD MIC) was 87.5% (95% CI: 73.0%-95.4%).</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0186424"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603657","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":"Mechanistic insights into the multitarget synergistic efficacy of farrerol and β-lactam antibiotics in combating methicillin-resistant <i>Staphylococcus aureus</i>.","authors":"Hangqian Yu, Li Wang, Xin Liu, Jianze Zheng, Hua Xiang, Yanyang Zheng, Dongmei Lv, Jingjing Yang, Yuxin Zhang, Jiazhang Qiu, Dacheng Wang","doi":"10.1128/aac.01551-24","DOIUrl":"10.1128/aac.01551-24","url":null,"abstract":"<p><p>Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), a principal causative agent of infections worldwide, urgently requires innovative interventions to counter its increasing risk. The present study revealed the profound impact of farrerol (FA), a robust bioactive agent, on the virulence and resistance mechanisms of MRSA. Our in-depth investigation revealed that FA significantly mitigated the β-lactam resistance of MRSA USA300, an achievement attributed to its precise interference with the BlaZ and Pbp2a protein. Additionally, FA indirectly diminishes the oligomerization of PBP2a by disrupting pigment synthesis, further contributing to its efficacy. In addition, FA extends its functional footprint beyond resistance modulation, exhibiting substantial antivirulence efficacy through selective inhibition of the accessory gene regulator (Agr) system, thereby significantly curbing MRSA pathogenicity in A549 cell and murine models. This study comprehensively explored the multiple impacts of FA on MRSA, shedding light on its versatile role as a BlaZ suppressor, pigment synthesis regulator, and AgrA activity modulator. These intricate findings firmly position FA as a compelling therapeutic candidate for addressing MRSA infections in the clinic.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0155124"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963547/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522529","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":"Identification of novel thiazole derivatives as flaviviral protease inhibitors effective against Dengue (DENV2) and Japanese encephalitis viruses.","authors":"Sheikh Murtuja, Sayan Das, Indrani Das Jana, Deepak Shilkar, Gourav Rakshit, Biswatrish Sarkar, Barij Nayan Sinha, Rikeshwer Prasad Dewangan, Arindam Mondal, Venkatesan Jayaprakash","doi":"10.1128/aac.01651-24","DOIUrl":"10.1128/aac.01651-24","url":null,"abstract":"<p><p>Flaviviruses are the causative agents of viral hemorrhagic fever (VHF) globally and have demonstrated the capacity to result in fatal outcomes if not managed effectively. Among different types of flaviviruses, dengue (DENV) and Japanese encephalitis (JEV) viruses are the most common in tropical and subtropical countries. While vaccines have been developed and licensed for both DENV and JEV, effective treatment options remain sparse. Hence, there is a pressing need to develop small molecules that can target machineries crucial for virus replication and remain conserved across different flaviviruses, thereby could serve as a promising therapeutic option. This study outlines the synthesis of novel thiazole compounds as flavivirus NS2B-NS3 protease inhibitor and characterization of their antiviral activity against DENV and JEV. We synthesized a heterocyclic template derived from a substrate-based retrotripeptide dengue protease inhibitor, leading to 48 thiazole derivatives. Two compounds, 3aq and 3au demonstrated significant inhibition of dengue virus protease activity <i>in vitro</i>. Comprehensive characterization of these two compounds was conducted through biochemical assay, which revealed an uncompetitive mode of inhibition. Subsequent cell-based assays using Dengue and Japanese encephalitis viruses as representative flaviviruses revealed the potential of these compounds to block viral RNA synthesis, and viral replication exhibiting 50% inhibitory concentrations (IC50s) in the low-micromolar range. Time-course experiments unveiled that the two compounds impeded the accumulation of viral genomic RNA primarily at later stages of infection, aligning with their capacity to hinder NS2B-NS3 protease activity, polyprotein processing and viral genomic RNA replication. Finally, time of addition experiment showed the compounds remain effective even when added 9 hpi, thereby confirming their potential as promising antivirals. Together, our work presents the development and validation of flavivirus protease inhibitors with therapeutic potential against Dengue (DENV2) and Japanese encephalitis viruses.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0165124"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482058","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":"Incidence of fidaxomicin allergy in patients with macrolide allergies: a large database analysis.","authors":"Chia-Yu Chiu, Daniel B Chastain, Madison E Salam, Joseph Sassine, Andrés F Henao-Martínez","doi":"10.1128/aac.01924-24","DOIUrl":"10.1128/aac.01924-24","url":null,"abstract":"<p><p>Fidaxomicin may exhibit cross-reactivity in patients with known macrolide allergies. In this analysis, compared to patients without macrolide allergies, the odds of fidaxomicin allergy were 2.31, 8.37, and 1.58 times higher in patients with azithromycin, clarithromycin, and erythromycin allergies, respectively; the absolute risk of fidaxomicin allergy was 0.033, 0.01, and 0.039 in patients with azithromycin, clarithromycin, and erythromycin allergies, respectively. The highest risk of anaphylaxis and angioedema was observed within 1 year of a non-fidaxomicin macrolide allergy.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0192424"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539950","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":"A phase I, single-center, randomized, open-label, three-period crossover study to evaluate the drug-drug interaction between ZSP1273 and oseltamivir in healthy Chinese subjects.","authors":"Yanqing Pang, Haijun Li, Xuemei Chen, Yingying Cao, Hui Jiang, Jufang Huang, Yiming Liu","doi":"10.1128/aac.01729-24","DOIUrl":"10.1128/aac.01729-24","url":null,"abstract":"<p><p>ZSP1273 is a novel small-molecule anti-influenza drug that targets the RNA polymerase PB2 subunit, while oseltamivir is the first-line medication that inhibits neuraminidase. ZSP1273 showed high efficacy against human influenza viruses both <i>in vitro</i> and <i>in vivo</i>, including oseltamivir-resistant strains <i>in vitro</i>. In future clinical applications, the combination of these two antiviral drugs with different mechanisms can reduce the potential for antiviral resistance that may arise from monotherapy. To evaluate the drug-drug interaction between ZSP1273 and oseltamivir by the pharmacokinetics and safety of co-administration in healthy subjects, a phase I, single-center, randomized, open-label, three-period crossover study was conducted. Thirty-six subjects enrolled were randomized in a 1:1:1 ratio into three crossover treatment sequences with oral administration detailed as follows: treatment A: ZSP1273 tablets 600 mg once daily (QD) for 5 days; treatment B: oseltamivir capsules 75 mg twice daily (BID) for 5 days; treatment C: ZSP1273 tablets 600 mg once daily (QD) + oseltamivir capsules 75 mg twice daily (BID) for 5 days. Plasma samples were collected from all subjects at scheduled time points after drug administration to measure the plasma concentrations of ZSP1273, oseltamivir, and its active metabolite oseltamivir carboxylate, for pharmacokinetic analysis. Compared with monotherapy, the geometric mean ratios (90% confidence intervals) of C_max,ss, AUC_0-t,ss, AUC_0-τ,ss, and AUC_0-∞,ss for ZSP1273 after co-administration were all within the ineffective boundary range of 80% to 125%, supporting that no drug-drug interaction occurs with ZSP1273. After co-administration, the AUC_0-t,ss, AUC_0-τ,ss, and AUC_0-∞,ss of oseltamivir were all within 80% to 125%, while C_max,ss decreased by 39.9%. The pharmacokinetic parameters above of oseltamivir carboxylate remained within 80%-125%, except only the lower bound of the 90% CI for C_max,ss slightly below 80% (77.0%). Considering the rapid metabolism of oseltamivir into the active metabolite oseltamivir carboxylate and the minor impact of co-administration on the pharmacokinetic parameters of oseltamivir carboxylate, it is believed that no clinically significant drug-drug interaction was observed with the combination of these two drugs. During the trial, the safety and tolerability of both combination therapy and monotherapy were good, with no increased safety risks observed from the combination therapy.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT05108051.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0172924"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482118","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":"Efficacy, safety, and anti-inflammatory properties of the switch to a doravirine-based regimen among antiretroviral-experienced elderly people living with HIV-1: the DORAGE cohort.","authors":"Alessandro Lazzaro, Gregorio Egidio Recchia, Federica Alessi, Letizia Santinelli, Luigi Battistini, Julieta Morcos, Francesco Romano, Ginevra Bugani, Luca Maddaloni, Sara Caruso, Marta D'Amico, Ivano Mezzaroma, Mario Falciano, Caterina Fimiani, Germana Sfara, Maria Gemma Leone, Ombretta Turriziani, Claudio Maria Mastroianni, Gabriella d'Ettorre","doi":"10.1128/aac.00815-24","DOIUrl":"10.1128/aac.00815-24","url":null,"abstract":"<p><p>Doravirine (DOR) is a novel antiretroviral agent with a favorable resistance profile and high tolerability. However, evidence is limited on DOR among elderly people living with HIV (PLWH) and whether it might modulate chronic inflammation. We aimed to investigate the efficacy, safety, and tolerability of DOR as a switching strategy among elderly PLWH and its impact on chronic inflammation in a real-life setting. We recruited a cohort of ART-experienced PLWH undergoing a therapeutic switch to a DOR-based regimen under virologic control (defined as HIV-RNA <200 copies/mL), regardless of the previous ART regimen. The primary objective was the evaluation of the rate of virologic control at 48 weeks post-switch. Secondary objectives included analyzing immune and metabolic outcomes. Plasmatic hs-CRP, IL-6, and D-dimer levels were measured as chronic inflammation markers. Overall, 150 PLWH were screened, and 147 were enrolled into the study. A total of 134 PLWH completed the follow-up. The rate of virological control was 96.1% (122/134; <i>CIs</i>: 91.0%-98.7%) in the per-protocol analysis. After 48 weeks from the switch, we recorded significant reductions in serum fasting glycemia (<i>P</i> 0.019), triglycerides (<i>P</i> 0.024), and total cholesterol/HDL ratio (<i>P</i> 0.017); no clinically significant differences were detected in the body weight and BMI, as long as in immune, hepatic, and renal profiles. A significant reduction in IL-6 (<i>P</i> 0.019) and hs-CRP (<i>P</i> 0.019) was observed. DOR is an effective and safe treatment choice for elderly PLWH. The intriguing modulatory effect of DOR-based regimens on chronic systemic inflammation deserves further investigation.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0081524"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439342","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":"Mutant prevention concentrations and phenotypic and genomic profiling of first-step resistance mechanisms to classical and novel β-lactams in <i>Pseudomonas aeruginosa</i>.","authors":"Miquel Àngel Sastre-Femenia, Maria Antonia Gomis-Font, Antonio Oliver","doi":"10.1128/aac.01942-24","DOIUrl":"10.1128/aac.01942-24","url":null,"abstract":"<p><p>A growing number of novel antipseudomonal β-lactams have been introduced in recent years, but the emergence of resistance is still a major concern in the treatment of <i>Pseudomonas aeruginosa</i> infections. Here, we compared the mutant prevention concentrations (MPCs) and the nature of first-step resistant mutants to classical and novel β-lactams in <i>P. aeruginosa</i>. MPCs were determined in duplicate experiments for ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, imipenem, imipenem/relebactam, meropenem, meropenem/vaborbactam, aztreonam, aztreonam/avibactam, and cefiderocol in PAO1, PAOMS (Δ<i>mutS</i>), and three extensively drug-resistant (XDR) clinical strains belonging to high-risk clones ST111, ST175, and ST235. Four mutants per strain and antibiotic, obtained from the highest concentration showing growth, were characterized through the determination of the susceptibility profiles and whole genome sequencing. Imipenem/relebactam presented the lowest MPC values, followed by ceftolozane/tazobactam. Overall, the MICs of the mutants were consistent with the antibiotic selection concentration, except for cefiderocol, which were much lower. MPCs were lower for ceftazidime/avibactam and imipenem/relebactam than those of the corresponding β-lactam alone. In contrast, MPCs of meropenem ± vaborbactam and aztreonam ± avibactam were identical in most strains. Ceftolozane/tazobactam and ceftazidime/avibactam derivatives presented mutations in <i>ampC</i>, <i>galU</i>, <i>cpxRS,</i> and/or in <i>bla_OXA-2</i> when present in the parent strain (ST235). Cefiderocol mutants were mainly defective in iron-uptake systems, particularly PiuA/DC. All carbapenems had oprD as the first-step mechanism. Imipenem/relebactam, meropenem ± vaborbactam, and aztreonam ± avibactam selected mutations frequently included efflux pumps and regulators. Imipenem ± relebactam also selected <i>aroB</i> mutations. This work first describes the MPCs and first-step resistance mechanisms for classical and novel β-lactams in <i>P. aeruginosa</i>. The identified shared and differential resistance development patterns between the available classical and novel β-lactams should be helpful to guide treatment strategies for XDR <i>P. aeruginosa</i> infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0194224"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603659","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":"Usefulness of a hub and spoke TDM-guided expert clinical pharmacological advice program of dalbavancin for optimizing very long-term curative or suppressive treatment of chronic staphylococcal infections.","authors":"Pier Giorgio Cojutti, Milo Gatti, Sara Tedeschi, Eleonora Zamparini, Marianna Meschiari, Maria Danzi, Giacomo Menegotto, Marco Cotrufo, Laura Soavi, Erika Chiari, Marco Ripa, Maria Mazzitelli, Massimo Crapis, Annamaria Cattelan, Giustino Parruti, Alessandro Russo, Lorenzo Zammarchi, Carlo Tascini, Pierluigi Viale, Federico Pea","doi":"10.1128/aac.01830-24","DOIUrl":"10.1128/aac.01830-24","url":null,"abstract":"<p><p>A hub and spoke model for optimizing long-term treatment of chronic staphylococcal infections with dalbavancin based on therapeutic drug monitoring (TDM)-guided expert clinical pharmacological advice (ECPA) was implemented. This multicentric retrospective cohort study included patients receiving dalbavancin monotherapy lasting >6 weeks at different spoke hospitals having treatment optimized by means of a TDM-guided ECPA program at a hub hospital. Optimal pharmacokinetic/pharmacodynamic target against staphylococci with an MIC up to 0.125 mg/L was defined as dalbavancin concentrations >8.04 mg/L. Patients received dalbavancin therapy for curative (curative group) or suppressive (suppressive group) purposes. Clinical outcome was assessed by means of repeated ambulatory visits. A total of 12 spoke hospitals applied for 414 TDM-based ECPA for 101 patients, of whom 64.4% (65/101) were treated for curative and 35.6% (36/101) were for suppressive purposes. In the curative and suppressive groups, TDM-based ECPA optimized treatment for up to 14 and 28 months, respectively, and ensured median optimal exposure of 95.7% and 100%, respectively. In the curative group, having <70% of treatment time with concentrations above the optimal target increased failure risk [odds ratio (OR), 6.71; confidence interval (CI), 0.97-43.3; <i>P</i> = 0.05]. In the suppressive group, infective endocarditis was associated with an increased risk of ineffective treatment (OR, 8.65; CI, 1.29-57.62; <i>P</i> = 0.046). Mild adverse events were reported in 4.5% (5/101) of cases. A hub and spoke TDM-guided ECPA program of dalbavancin may be cost-effective for optimizing long-term treatment of chronic staphylococcal infections and for patients admitted to hospitals lacking in-house MD clinical pharmacologists.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0183024"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482136","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":"2024 Acknowledgment of AAC Reviewers.","authors":"Cesar A Arias","doi":"10.1128/aac.00334-25","DOIUrl":"https://doi.org/10.1128/aac.00334-25","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":"69 4","pages":"e0033425"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762842","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":"Pharmacokinetics, tolerability, and safety of TBI-223, a novel oxazolidinone, in healthy participants.","authors":"Antonio Lombardi, Fran Pappas, Paul Bruinenberg, Jerry Nedelman, Rajneesh Taneja, Dean Hickman, Maria Beumont, Eugene Sun","doi":"10.1128/aac.01542-24","DOIUrl":"10.1128/aac.01542-24","url":null,"abstract":"<p><p>TBI-223 is an oxazolidinone antibiotic under clinical development for the treatment of tuberculosis. Preclinical data indicate potent antituberculosis activity and a potentially improved safety profile over linezolid. In a single-ascending dose study and a multiple-ascending dose study in 114 healthy adults, TBI-223 was generally safe and well tolerated at single doses up to 2,600 mg and multiple doses up to 2,400 mg daily over 14 days. No deaths, serious or severe adverse events, or discontinuations resulting from adverse effects (other than COVID-19) occurred. Except for two instances of orthostatic tachycardia in the single-ascending dose (SAD) study that resolved, no clinically significant electrocardiogram changes were noted. Concentration-QTc modeling found significant relationships of QTc with concentrations of TBI-223 and its main metabolite. However, groups receiving TBI-223 experienced QTc > 450 ms at a similar rate to those receiving placebo. TBI-223 exposures were nearly dose proportional. In the SAD study, TBI-223 exhibited a terminal half-life of 1.9-3.8 hours. Sustained-release tablets achieved a mean AUC_0-inf of 70%-80% relative to immediate-release tablets, with more than 50% lower mean <i>C</i>_max. These results support further investigation of TBI-223 for the treatment of tuberculosis.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03758612 and NCT04865536.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0154224"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603661","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}