Antimicrobial Agents and Chemotherapy最新文献

{"title":"How accurate is ceftriaxone at predicting susceptibility of enterobacterales isolates to oral higher-generation cephalosporins?","authors":"Kimberly C Claeys, Patricia J Simner, Tsigereda Tekle, Anthony D Harris, Emily Jacobs, Sara E Cosgrove, Pranita D Tamma","doi":"10.1128/aac.01387-24","DOIUrl":"10.1128/aac.01387-24","url":null,"abstract":"<p><p>The reliability of ceftriaxone for inferring susceptibility to higher-generation oral cephalosporins is unknown. Overall, ceftriaxone susceptibility predicted susceptibility to cefuroxime (89%), cefdinir (86%), cefpodoxime (90%), and cefixime (94%) based on disk diffusion results for 409 consecutive Enterobacterales bloodstream isolates from unique patients. Susceptibility percentages to the four oral cephalosporins ranged from 92% to 99% when limited to <i>Escherichia coli</i>, <i>Klebsiella pneumoniae, Klebsiella oxytoca, or Proteus mirabilis</i> isolates susceptible to ceftriaxone.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0138724"},"PeriodicalIF":4.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823661/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913543","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":"<i>In vitro</i> potentiation of tetracyclines in <i>Pseudomonas aeruginosa</i> by RW01, a new cyclic peptide.","authors":"Natalia Roson-Calero, María A Gomis Font, Albert Ruiz-Soriano, Xavier Just-Baringo, María Eugenia Pachón-Ibáñez, J Pablo Salvador, M Pilar Marco, Ernest Giralt, Antonio Oliver, Clara Ballesté-Delpierre, Jordi Vila","doi":"10.1128/aac.01459-24","DOIUrl":"10.1128/aac.01459-24","url":null,"abstract":"<p><p>The pipeline for new drugs against multidrug-resistant <i>Pseudomonas aeruginosa</i> remains limited, highlighting the urgent need for innovative treatments. New strategies, such as membrane-targeting molecules acting as adjuvants, aim to enhance antibiotic effectiveness and combat resistance. RW01, a cyclic peptide with low antimicrobial activity, was selected as an adjuvant to enhance drug efficacy through membrane permeabilization. RW01's activity was evaluated via antimicrobial susceptibility testing in combination with existing antibiotics on 10 <i>P. aeruginosa</i> strains and analog synthesis. Synergy was assessed using checkerboard assays, and one-step mutants were generated to identify altered pathways through whole-genome sequencing and variant analysis. Permeabilizing activity was studied using flow cytometry and real-time fluorescence measurement. <i>In vivo</i> toxicity was assessed in female C57BL/6J mice, and possible interaction with mouse serum was also evaluated. Susceptibility testing revealed specific synergy with tetracyclines, with up to a 16-fold reduction in minimum inhibitory concentrations. Sequencing revealed that resistance to the RW01-minocycline combination involved mutations in the <i>pmrB</i> gene, affecting outer membrane lipopolysaccharide composition. This was further confirmed by the identification of cross-resistance to colistin in these mutants. RW01 reduced the mutant prevention concentration of minocycline from 64 to 8 mg/L. RW01 was demonstrated to enhance membrane permeabilization and therefore minocycline uptake with statistical significance. Synthetic derivatives of RW01 showed a complete loss of activity, highlighting the importance of RW01's D-proline(NH2) residue. No acute or cumulative <i>in vivo</i> toxicity was observed in mice. These findings suggest that RW01 could revitalize obsolete antimicrobials and potentially expand therapeutic options against multidrug-resistant <i>P. aeruginosa</i>.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0145924"},"PeriodicalIF":4.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876092","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":"Bacteriophage treatment is effective against carbapenem-resistant <i>Klebsiella pneumoniae</i> (KPC) in a neutropenic murine model of gastrointestinal translocation and renal infection.","authors":"Panagiotis Zagaliotis, Jordyn Michalik-Provasek, Eleftheria Mavridou, Ethan Naing, Ioannis S Vizirianakis, Dimitrios Chatzidimitriou, Jason J Gill, Thomas J Walsh","doi":"10.1128/aac.00919-24","DOIUrl":"10.1128/aac.00919-24","url":null,"abstract":"<p><p>Carbapenemase-producing <i>Klebsiella pneumoniae</i> (KPC) are globally emerging pathogens that cause life-threatening infections. Novel treatment alternatives are urgently needed. We therefore investigated the effectiveness of three novel bacteriophages (Spivey, Pharr, and Soft) in a neutropenic murine model of KPC gastrointestinal colonization, translocation, and disseminated infection. Bacteriophage efficacy was determined by residual bacterial burden of KPC (CFU/g) in kidneys. Parallel studies were conducted of bacteriophage pharmacokinetics and resistance. Treatment of mice with 5 × 10⁹ PFU of phage cocktail via intraperitoneal injection was effective in significantly reducing renal KPC CFU by 100-fold (<i>P</i> < 0.01) when administered every 24 h and 1000-fold (<i>P</i> < 0.01) every 12 h. Moreover, a combination of bacteriophage and ceftazidime-avibactam produced a synergistic effect, resulting in a 10⁵-fold reduction in bacterial burden in cecum and kidney (<i>P</i> < 0.001 in both tissues). Prophylactic administration of bacteriophages via oral gavage did not prevent KPC translocation to the kidneys. Bacteriophage decay determined by linear regression of the ln of mean concentrations demonstrated R² values in plasma of 0.941, kidney 0.976, and cecum 0.918, with half-lives of t_1/2 = 2.5 h. Furthermore, a phage-resistant mutant displayed increased sensitivity to serum killing <i>in vitro</i>, but did not show significant defects in renal infection <i>in vivo</i>. A combination of bacteriophages demonstrated significant efficacy alone and synergy with ceftazidime/avibactam in the treatment of experimental disseminated KPC infection in neutropenic mice.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0091924"},"PeriodicalIF":4.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823626/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862907","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":"Increasing rates of <i>erm</i>(B) and <i>erm</i>(N) in human <i>Campylobacter coli</i> and <i>Campylobacter jejuni</i> erythromycin-resistant isolates between 2018 and 2023 in France.","authors":"Quentin Jehanne, Lucie Bénéjat, Astrid Ducournau, Johanna Aptel, Marie Pivard, Léo Gillet, Marine Jauvain, Philippe Lehours","doi":"10.1128/aac.01668-24","DOIUrl":"10.1128/aac.01668-24","url":null,"abstract":"<p><p>Macrolides are the first-line compounds used for the treatment of campylobacteriosis. Macrolide resistance remains low in France, with mutations in <i>23S rDNA</i> being the main associated resistance mechanism. However, two erythromycin methyltransferases have also been identified<i>: erm</i>(B), which is mainly described in animal reservoirs, and <i>erm</i>(N), which is strictly described in humans. In France, between 2018 and 2023, erythromycin-resistant <i>Campylobacter</i> species strains were systematically sequenced and analyzed <i>via</i> an in-house bioinformatics pipeline, leading to the identification of the resistomes, MLST and cgMLST, as well as the characterization of the source of contamination. In this study, the genomes of 280 erythromycin-resistant strains were sequenced over a 6-year period. The identification of erythromycin-associated resistance markers revealed a predominance of <i>23S rDNA</i> mutations, in 90% of cases, but also <i>erm</i>-type methyltransferases in 10% of cases: 75% for <i>erm</i>(N) and 25% for <i>erm</i>(B). Over this period, an important increase in the rate of <i>erm</i>-positive isolates was observed: 2% in 2018 compared with 13% in 2023, with 10% for <i>erm</i>(N) and 3% for <i>erm</i>(B). <i>erm</i>(N) has been found exclusively within a CRISPR-Cas9 operon, whereas <i>erm</i>(B) has been found within diverse types of resistance genomic islands. Each <i>erm</i>(N)- or <i>erm</i>(B)-positive isolate had at least two other resistance markers (mostly ciprofloxacin, tetracycline, or ampicillin) and often carried aminoglycoside-associated resistance genes. The majority of the <i>erm</i>-positive isolates were obtained from chicken. The increasing rates of <i>erm</i>-positive and multiresistant isolates make the monitoring of erythromycin-resistant <i>Campylobacter</i> strains, specifically within the chicken meat production, a topic of serious importance.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0166824"},"PeriodicalIF":4.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913551","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":"Evaluation of the safety profile and intrapulmonary pharmacokinetics of intravenous fosfomycin in healthy adults.","authors":"Lindsay Boole, Zhonghui Yang, Stephen P Bergin, Robert M Tighe, Emily Randolph, Byron Hauser, Kenan Gu, Varduhi Ghazaryan, Alison Wall, Katherine Weigand, Emmanuel B Walter, Loretta G Que","doi":"10.1128/aac.01395-24","DOIUrl":"10.1128/aac.01395-24","url":null,"abstract":"<p><p>This Phase 1 trial described the intrapulmonary pharmacokinetics and safety profile of IV fosfomycin in healthy participants<i>.</i> Fosfomycin, a broad-spectrum antibiotic mainly used to treat urinary tract infections, is being considered for treatment of more complex conditions, including lung infections, due to the emergence of multidrug-resistant (MDR) organisms. Despite its potential, the pharmacokinetics and safety profile of intravenous (IV) fosfomycin, particularly its penetration into the lower respiratory tract, are unknown. To address this gap, we conducted a Phase 1, open-label trial to assess the safety and pulmonary pharmacokinetics of IV fosfomycin in healthy participants. Thirty-seven healthy volunteers aged 18-45 years received three doses of 6 g IV fosfomycin every 8 hours. Bronchoscopy with bronchoalveolar lavage (BAL) was performed at randomly assigned time points after the third dose. BAL fluid, BAL cell pellets, and blood plasma samples for fosfomycin were analyzed using validated assays of liquid chromatography with tandem mass spectrometry (LC-MS/MS). Adverse events (AEs) were assessed. Fosfomycin exhibited penetration into alveolar macrophages (AM) at a rate of 16.8% and into the extracellular lining fluid (ELF) at 30.8%. Mean AM fosfomycin concentration ranged from 14.8 to 32 μg/mL, while the mean ELF concentration ranged from 15.7 to 82.5 μg/mL. All participants experienced at least one treatment-emergent adverse event (TEAE), mostly mild/grade 1, with no serious adverse events (SAEs) reported. Intravenous fosfomycin effectively penetrates both the extracellular (ELF) and intracellular (AM) compartments of the lower respiratory tract in healthy participants. The overall tolerability of IV fosfomycin was favorable, suggesting its potential as an effective antibacterial treatment for lower respiratory tract infections.</p><p><strong>Clinical trials: </strong>This study is registered with ClinicalTrials.gov as NCT03910673.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0139524"},"PeriodicalIF":4.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142943342","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":"Population pharmacokinetics of piperacillin-tazobactam in the plasma and cerebrospinal fluid of critically ill patients.","authors":"Nilesh Kumta, Aaron J Heffernan, Menino Osbert Cotta, Xin Liu, Suzanne Parker, Steven Wallis, Amelia Livermore, Therese Starr, Wai Tat Wong, Gavin M Joynt, Jeffrey Lipman, Jason A Roberts","doi":"10.1128/aac.00601-24","DOIUrl":"10.1128/aac.00601-24","url":null,"abstract":"<p><p>Ventriculitis in neurocritical care patients leads to significant morbidity and mortality. Antibiotic dose optimization targeting pharmacokinetic/pharmacodynamic (PK/PD) exposures associated with improved bacterial killing may improve therapeutic outcomes. We sought to develop and apply a population PK model in infected critically ill patients to determine optimal piperacillin-tazobactam (PTZ) dosing regimens to achieve target cerebrospinal fluid (CSF) exposures. Neurosurgical patients with external ventricular drains and receiving PTZ treatment were recruited and had plasma and CSF samples collected and assayed. A population PK model was developed using plasma and CSF piperacillin and tazobactam concentrations. Eight patients were recruited. Median age was 59 years, median weight was 70 kg, and five patients were female. The median creatinine clearance was 84 mL/min/1.73 m² (range 52-163). Substantial inter-individual PK variability was apparent, particularly in CSF. Piperacillin penetration into CSF had a median of 3.73% (range 0.73%-7.66%), and tazobactam CSF penetration was not predictable. Dosing recommendations to optimize CSF exposures for the treatment of ventriculitis were not possible due to substantial PK variability and very low drug penetration. High plasma PTZ exposures may not translate to effective exposures in CSF.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0060124"},"PeriodicalIF":4.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852200","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":"Impact of the inoculum size on the <i>in vivo</i> activity of the aztreonam-avibactam combination in a murine model of peritonitis due to <i>Escherichia coli</i> expressing CTX-M-15 and NDM-1.","authors":"Ariane Amoura, Laura Benchetrit, Sophie Magréault, Samuel Chosidow, Alice Le Menestrel, Vincent Jullien, Victoire de Lastours, Françoise Chau, Sara Dion, Laurent Massias, Bruno Fantin, Agnès Lefort","doi":"10.1128/aac.01288-22","DOIUrl":"10.1128/aac.01288-22","url":null,"abstract":"<p><p>The combination of aztreonam (ATM) and avibactam (AVI) is an attractive option to treat infections caused by extended spectrum β-lactamase plus NDM-1-producing <i>Enterobacteriaceae</i>. Since ATM activity was shown to be severely impacted by an increase in the inoculum size <i>in vitro</i>, we wondered whether ATM-AVI activity could be impaired in high-inoculum infections. We analyzed the impact of the inoculum size on ATM-AVI activity <i>in vitro</i> and in a murine model of peritonitis due to susceptible <i>Escherichia coli</i> CFT073-pTOPO and its isogenic derivatives producing NDM-1 (<i>E. coli</i> CFT073-NDM1) and CTX-M-15 plus NDM-1 (<i>E. coli</i> CFT073-CTXM15-NDM1). The impact of the inoculum size on bacterial morphology was studied by microscopic examination. <i>In vitro</i>, at standard (10⁵) inoculum, <i>E. coli</i> CFT073-CTXM15-NDM1 was resistant to ATM but susceptible to the ATM-AVI combination. At high (10⁷) inoculum, MICs of ATM alone and of the ATM-AVI combination reached >512 and 64 mg/L, respectively, against all tested strains. ATM led to bacterial filamentation when active against the bacteria, i.e., in monotherapy or in combination with AVI against susceptible <i>E. coli</i> CFT073-pTOPO and only in combination with AVI against <i>E. coli</i> CFT073-CTXM15-NDM1. <i>In vivo</i>, increase in the inoculum led to a drastic decrease in the activity of ATM alone against <i>E. coli</i> CFT073-pTOPO and ATM-AVI against <i>E. coli</i> CFT073-CTXM15-NDM1. Our results suggest a high <i>in vivo</i> impact of the inoculum increase on the activity of ATM alone against ATM-susceptible <i>E. coli</i> and of ATM-AVI against CTX-M-15 plus NDM-1 producing <i>E. coli</i>. Clinicians must be aware of the risk of failures when using ATM-AVI in high-inoculum infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0128822"},"PeriodicalIF":4.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852194","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":"Population pharmacokinetics of caspofungin in critically ill patients receiving extracorporeal membrane oxygenation-an ASAP ECMO study.","authors":"Mohd H Abdul-Aziz, Arne Diehl, Xin Liu, Vesa Cheng, Amanda Corley, Eileen Gilder, Bianca Levkovich, Shay McGuinness, Jenny Ordonez, Rachael Parke, Vincent Pellegrino, Steven C Wallis, John F Fraser, Kiran Shekar, Jason A Roberts","doi":"10.1128/aac.01435-24","DOIUrl":"10.1128/aac.01435-24","url":null,"abstract":"<p><p>This study aimed to describe the population pharmacokinetics of caspofungin in critically ill patients receiving extracorporeal membrane oxygenation (ECMO) and to identify dosing regimens with a high likelihood of achieving effective exposures. Serial blood samples were collected over a single-dosing interval during ECMO. Total plasma concentrations were measured by a validated chromatographic assay. A population pharmacokinetic model was built and Monte Carlo dosing simulations were performed using Monolix. The probability of target attainment (PTA) and fractional target attainment (FTA) rates were simulated for various caspofungin dosing regimens against <i>Candida albicans</i>, <i>Candida glabrata</i>, and <i>Candida parapsilosis</i>. In all, 64 plasma concentration-time points were obtained from 8 critically ill patients receiving ECMO. Plasma concentration-time data for caspofungin were best described by a one-compartment model with first-order elimination. Lean body weight was identified as a significant covariate of volume of distribution. The typical volume of distribution and clearance of caspofungin in this cohort were 8.13 L and 0.55 L/h, respectively. The licensed caspofungin dosing regimen (a loading dose of 70 mg on day 1 followed by a maintenance dose of either 50 mg/day or 70 mg/day) demonstrated optimal PTA rates (≥90%) against <i>C. albicans</i> with an MIC of ≤0.064 mg/L, <i>C. glabrata</i> with an MIC of ≤0.125 mg/L, and <i>C. parapsilosis</i> with an MIC of ≤0.064 mg/L. The FTA analysis suggested that the licensed dosing regimen is only optimal (≥95%) against <i>Candida glabrata</i>, regardless of lean body weight. A higher-than-standard empirical dosing regimen (e.g., a loading dose of 100 mg on day 1, followed by a maintenance dose of 100 mg daily) is likely advantageous for critically ill patients receiving ECMO.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0143524"},"PeriodicalIF":4.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845683","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":"Fluoroquinolones and rifampin combination in the backdrop of heteroresistant tuberculosis.","authors":"Vanessa B Vogensen, Sanjay Singh, Christopher J Allende, David M Engelthaler, Gunavanthi D Boorgula, Tania A Thomas, Marieke G G Sturkenboom, Onno W Akkerman, Tawanda Gumbo, Shashikant Srivastava","doi":"10.1128/aac.01084-24","DOIUrl":"10.1128/aac.01084-24","url":null,"abstract":"<p><p>The impact of heteroresistance on tuberculosis (TB) treatment outcomes is unclear, as is the role of different rifampin and isoniazid exposures on developing resistance mutations. Hollow fiber system model of TB (HFS-TB) units were inoculated with drug-susceptible <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) and treated with isoniazid and rifampin exposure identified in a clinical trial as leading to treatment failure and acquired drug resistance. Systems were sampled for drug concentration measurements, estimation of total and drug-resistant <i>Mtb</i>, and small molecule overlapping reads (SMOR) analysis for the detection of heteroresistance. In the second HFS-TB study, systems were inoculated with an isoniazid-resistant clinical strain and treated with various combinations of isoniazid, rifampin, moxifloxacin, and levofloxacin for 28 days. Linear regression and exponential decline models were used for data analysis. Suboptimal isoniazid and rifampin exposures failed to kill drug-susceptible <i>Mtb</i> in the HFS-TB. Standard susceptibility methods failed to detect drug resistance, but SMOR detected isoniazid and rifampin heteroresistance, as well as fluoroquinolone, to which bacilli were not exposed. <i>rpoB</i> mutations arising from low rifampin exposures were Q513K and H526N, whereas those from regimen adequate rifampin but low isoniazid concentrations were S531L. Moxifloxacin-rifampin combination sterilized the HFS-TB units inoculated with the isoniazid-resistant <i>Mtb</i> in 14 days compared with 21 days of treatment with levofloxacin-rifampin, with no further emergence of drug resistance. Early detection of isoniazid and rifampin heteroresistance could provide an opportunity to individualize the therapy and protect fluoroquinolones when added to the MDR-TB treatment regimen.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0108424"},"PeriodicalIF":4.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999070","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":"Single-dose tolerability and pharmacokinetics of leritrelvir in Chinese patients with hepatic impairment and healthy matched controls.","authors":"Cuiyun Li, Jiajia Mai, Min Wu, Hong Zhang, Xiaojiao Li, Haijun Li, Youyun Li, Yanhua Ding","doi":"10.1128/aac.01377-24","DOIUrl":"10.1128/aac.01377-24","url":null,"abstract":"<p><p>This study evaluated the safety and pharmacokinetics (PK) of a single dose of leritrelvir, a novel inhibitor of 3-chymotrypsin-like cysteine protease (3CLpro), in patients with hepatic impairment versus healthy participants with normal hepatic function. Eight participants with mild (Child-Pugh A) hepatic impairment, eight with moderate (Child-Pugh B) hepatic impairment, and eight healthy matched control participants were enrolled in this open-label, parallel clinical trial. After administration of leritrelvir of 400 mg, PK parameters were calculated and compared across groups. In total, 24 participants were enrolled and completed the study. Leritrelvir was generally well tolerated, with no serious adverse events or deaths reported during the study. Compared to the group with normal hepatic function, the geometric least-squares mean ratios (90% confidence intervals) for <i>C</i>_max, AUC_0-<i>t</i>, and AUC_0-∞ of leritrelvir in participants with mild hepatic impairment were 96.9% (69.3%, 135%), 92.2% (69.6%, 122%), and 92.1% (69.7%, 122%), respectively. For moderate hepatic impairment, the corresponding ratios were 91.6% (61.7%, 136%), 113% (80.0%, 160%), and 113% (80.0%, 159%). Leritrelvir exposures were comparable among the three groups. Overall, there was no clinically relevant difference in leritrelvir exposure in participants with hepatic impairment compared to normal controls. No dose adjustment is required for leritrelvir in patients with mild or moderate hepatic impairment.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT06161259.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0137724"},"PeriodicalIF":4.1,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833524","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}