Antimicrobial Agents and Chemotherapy最新文献

{"title":"The two-component system CrdRS mediates sub-inhibitory antibiotic-induced biofilm formation in <i>Helicobacter pylori</i> via bidirectional regulation of transporters PlpA and GlnP.","authors":"Wenxin Zhang, Lu Zhang, Yanlin Sun, Mingzhong Zhao, Shujing Xu, Han Yu, Wenjing Wang, Jinmeng Liu, Wenyue Ma, Xiaoyu Wang, Ziyan Zhang, Yundong Sun","doi":"10.1128/aac.00882-26","DOIUrl":"https://doi.org/10.1128/aac.00882-26","url":null,"abstract":"<p><p>Biofilm formation by <i>Helicobacter pylori</i> is a major driver of antibiotic tolerance and treatment failure, yet the signaling pathways that trigger biofilm development under sub-inhibitory antibiotic pressure remain poorly understood. Here, we show that sub-MIC levels of metronidazole, amoxicillin, and ciprofloxacin potently induce dense <i>H. pylori</i> biofilms. Through transcriptomic and genetic analyses, we identify the two-component system CrdRS as a central signaling hub that orchestrates this response via the bidirectional regulation of two ATP-binding cassette (ABC) transporters. Phosphorylated CrdR binds to AC-rich promoter motifs to directly activate <i>plpA</i>, which encodes a substrate-binding protein that drives exopolysaccharide secretion and matrix assembly. Concomitantly, CrdR represses <i>glnP</i>, which encodes an inner-membrane permease, thereby relieving transcriptional inhibition of the L-asparaginase gene <i>ansB</i>. This derepression triggers aberrant reactive oxygen species (ROS) accumulation, which promotes oxidative stress-dependent biofilm maturation. Through phenotypic analysis of c<i>rdRS</i> deletion mutants, phosphorylation-defective point mutants (CrdR^D53A and CrdS^H173A), and exogenous hydrogen peroxide (H₂O₂) induction, we demonstrate that CrdRS is required for mediating antibiotic-induced stress responses in a manner genetically separable from ROS sensing. Collectively, our findings establish a dual-mechanism model in which CrdRS orchestrates antibiotic-induced biofilm formation by simultaneously controlling matrix production and intracellular ROS generation. Notably, <i>glnP</i> expression was significantly lower in clinical multidrug-resistant isolates than in drug-sensitive ones, whereas <i>plpA</i> showed the opposite trend. These findings provide a mechanistic foundation for developing CrdRS-targeted strategies to combat biofilm-associated <i>H. pylori</i> infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0088226"},"PeriodicalIF":4.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103229","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":"Screening of a chemogenetic library unveils dual-stage antiplasmodials with low cytotoxicity.","authors":"Laura Torres, Matthew E Fishbaugher, Melanie Lam, Alexander T Chao, Calla Martyn, Luying Pei, Debapriya Sengupta, Maxime Dauphinais, Jonathan E Gable, Srinivasa P S Rao, Steffen Renner, W Armand Guiguemde, Sebastian A Mikolajczak, Anke Harupa, Gabriel Mitchell","doi":"10.1128/aac.01613-25","DOIUrl":"https://doi.org/10.1128/aac.01613-25","url":null,"abstract":"<p><p>The global effort to eradicate malaria requires the development of drugs with novel mechanisms of action and differentiated pharmacological profiles. Both liver and blood phases of <i>Plasmodium</i> infection are essential for disease progression and transmission, making them primary targets for pharmacological intervention. In this study, we established a dual-luciferase reporter assay to simultaneously assess <i>Plasmodium berghei</i> liver-stage development and host cell viability. Screening a library of bioactive small molecules with annotated human targets revealed several inhibitors with potent liver-stage activity and minimal cytotoxicity. Further profiling against <i>Plasmodium falciparum</i> asexual blood stages identified compounds with dual-stage activity, underscoring their potential utility for development as either prophylactic or therapeutic agents. Knowledge of their human targets will facilitate investigation into host- or parasite-directed antimalarial mechanisms, thereby accelerating both biological insight and rational drug development. Our findings constitute a valuable resource for research on malaria biology and the discovery of next-generation antiplasmodials.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0161325"},"PeriodicalIF":4.2,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103309","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":"Pulmonary pharmacokinetics and lesion penetration of antimicrobials in patients with nontuberculous mycobacterial disease.","authors":"Fumiya Watanabe, Miyako Hiramatsu, Toru Kawakami, Teruaki Oka, Hayato Nanami, Kiyomi Shimoda, Kazuhiko Hanada, Yuji Shiraishi, Kozo Morimoto","doi":"10.1128/aac.00820-26","DOIUrl":"https://doi.org/10.1128/aac.00820-26","url":null,"abstract":"<p><p>The intrapulmonary pharmacokinetics of antimicrobial agents used to treat nontuberculous mycobacterial (NTM) pulmonary disease remains poorly characterized, limiting the optimization of dosing regimens. This study characterized the plasma and intrapulmonary pharmacokinetics of azithromycin, ethambutol, rifampicin, clofazimine, and amikacin, as well as their penetration into pulmonary lesion sites. We prospectively enrolled patients undergoing guideline-based treatment for NTM pulmonary disease who were indicated for surgical resection at a single center in Japan. Drug concentrations were measured in the plasma and lung samples and analyzed using a population pharmacokinetic model. The lung lesion site, cavity, or nodule/bronchiectatic lesion was evaluated as covariates of the lung-to-plasma partition ratios. Twenty-four patients were enrolled in the study. The estimated lung-to-plasma partition coefficients and intrapulmonary half-lives were 535-fold and 6.3 months for azithromycin, 40-fold and 2.0 months for ethambutol, 5.2-fold and 6.3 min for rifampicin, 18,800-fold and 22 years for clofazimine, 1.3-fold and 2.3 h for intravenous amikacin, and 1.3-fold and 5.0 h for inhaled amikacin, respectively. Evaluation of drug penetration into cavities and nodular/bronchiectatic lesions showed no clearly reduced concentration compared to a normal lung tissue. The intrapulmonary pharmacokinetic characteristics identified in this study provide valuable information for optimizing antimicrobial dosing regimens in the treatment of NTM pulmonary disease. Furthermore, the absence of clearly reduced drug penetration into lesion sites suggests that lesion phenotype alone may have limited value in guiding antimicrobial selection.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0082026"},"PeriodicalIF":4.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103259","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":"Dermatophytes in Argentina: species distribution, comparative identification accuracy of conventional and proteomic methods, introduction of a novel molecular identification approach, and antifungal susceptibility profiles.","authors":"Natalia Sasoni, María Sol Barbagelata, Ivana Maldonado, Luciana Farias, Matias Cabeza, Manuela Loaiza-Oliva, María Gabriela Latorre Rapela, Soledad Gamarra, Norma Fernández, Guillermo García-Effron","doi":"10.1128/aac.00796-26","DOIUrl":"https://doi.org/10.1128/aac.00796-26","url":null,"abstract":"<p><p>Dermatophytosis is a frequent superficial fungal infection, yet data from Argentina remain scarce. In this multicenter study, 127 isolates consecutively collected in 2024 were analyzed using morphology, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, internal transcribed spacer sequencing, and a novel multiplex PCR assay for rapid identification. Predominant species included <i>Trichophyton tonsurans</i>, <i>Trichophyton rubrum</i>, and the <i>Trichophyton mentagrophytes</i> complex. Antifungal testing (CLSI M38) revealed interspecies variability: terbinafine was most active, itraconazole showed better efficacy against <i>Microsporum canis</i>, while fluconazole displayed limited activity.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0079626"},"PeriodicalIF":4.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103023","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":"G-quadruplex-binding ligand RHPS4 reduces <i>Plasmodium falciparum</i> mitochondrial DNA level providing a novel antimalarial strategy.","authors":"Mariam Salim, Lucie Paloque, Flore Nardella, Thibaud Reyser, Michel Nguyen, Jean-Michel Augereau, Yu Luo, Sébastien Britton, Jean-Louis Mergny, Virginie Gervais, Françoise Benoit-Vical, Dennis Gomez","doi":"10.1128/aac.00144-26","DOIUrl":"https://doi.org/10.1128/aac.00144-26","url":null,"abstract":"<p><p>Malaria caused by <i>Plasmodium falciparum</i> remains a major health threat, killing over 600,000 people annually. The spread of resistance to all major antimalarials, including artemisinins, highlights the urgent need for new drugs with distinct mechanisms of action. Here, we show that the G-quadruplex ligand RHPS4, an acridine derivative, displays strong antiplasmodial activity against both drug-sensitive and drug-resistant <i>P. falciparum</i> strains and clinical isolates. RHPS4 primarily targets the trophozoite stage and induces major mitochondrial alterations, including reduction of mitochondrial DNA (mtDNA) and transcriptional dysfunctions. Bioinformatic analyses identified at least eight putative G4-forming sequences within the parasite's mtDNA. Biophysical studies confirmed G4 folding of at least one sequence and its interaction with RHPS4. These findings indicate that RHPS4 impacts <i>P. falciparum</i> mitochondrial DNA replication and transcription, leading to parasite death, and establish G4 ligands as novel antimalarial agents.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0014426"},"PeriodicalIF":4.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103039","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":"OT-CATH, a conserved antimicrobial peptide in <i>Otariidae</i> species, exhibits potent activity against gram-negative bacteria.","authors":"Yixiao Song, Yufeng Ren, Juan Wang, Zifan Ye, Chenchen Shi, Xiangjin Kong, Xudong Jiao, Jingjing Zhang, Yipeng Wang","doi":"10.1128/aac.01026-26","DOIUrl":"https://doi.org/10.1128/aac.01026-26","url":null,"abstract":"<p><p>The rapid emergence of multidrug-resistant gram-negative bacteria necessitates the development of effective antimicrobial agents to combat antimicrobial resistance. Here, we identified and characterized OT-CATH, a conserved cathelicidin-family antimicrobial peptide derived from <i>Otariidae</i> species. OT-CATH exhibited potent bactericidal activity against gram-negative bacteria, particularly extended-spectrum β-lactamase-producing <i>Escherichia coli</i>, with rapid killing kinetics, potent antibiofilm activity, and no detectable resistance after 40 serial passages. Mechanistically, OT-CATH bound lipopolysaccharide, disrupted both the outer and inner bacterial membranes, and translocated into the cytoplasm to interact with bacterial DNA. Membrane disruption further triggered intracellular reactive oxygen species accumulation, proton motive force dissipation, ATP depletion, and metabolic collapse, collectively leading to bacterial death. OT-CATH also demonstrated favorable stability, low cytotoxicity, and favorable pharmacokinetic properties with measurable pulmonary distribution. In a murine pneumonia model, OT-CATH significantly improved survival, reduced bacterial burdens in the lungs and bronchoalveolar lavage fluid, and alleviated lung injury. These findings identify OT-CATH as a promising membrane-targeting antimicrobial peptide for the treatment of multidrug-resistant gram-negative bacterial infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0102626"},"PeriodicalIF":4.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149103276","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":"Relative inhibitory activities of taniborbactam and xeruborbactam against KPC variants conferring reduced susceptibility or resistance to ceftazidime/avibactam, cefiderocol, and cefepime/taniborbactam.","authors":"Salud Rodríguez-Pallares, Christophe Le Terrier, Tania Blanco-Martín, Roberto Rilo-Antelo, Cristina Elías-López, Lucía Sánchez-Peña, Carlos Molina-Cáceres, Gloria Pérez-Rodríguez, Lucía González-Pinto, Luis Martínez-Martínez, Laurent Poirel, Germán Bou, Jorge Arca-Suárez","doi":"10.1128/aac.00897-26","DOIUrl":"https://doi.org/10.1128/aac.00897-26","url":null,"abstract":"<p><p>The emergence of KPC variants associated with ceftazidime/avibactam resistance may also compromise the activity of other recently developed β-lactams, including cefiderocol and cefepime/taniborbactam. Xeruborbactam is a boronic acid β-lactamase inhibitor with potent activity against serine- and metallo-β-lactamases and is currently under clinical development in combination with cefiderocol. We evaluated the <i>in vitro</i> activity of cefiderocol/xeruborbactam against a panel of clinical <i>Klebsiella pneumoniae</i> isolates and isogenic <i>Escherichia coli</i> transformants (including both wild-type and porin-deficient backgrounds) producing KPC variants. Xeruborbactam and taniborbactam activities were compared using ceftazidime, cefepime, and cefiderocol as reporter substrates. Inhibitory activity was analyzed by determining the IC₅₀ values for both inhibitors against KPC variants. Most clinical isolates producing KPC variants showed increased MIC values and substantial cross-resistance to ceftazidime/avibactam, cefiderocol, and cefepime/taniborbactam. Cefiderocol/xeruborbactam retained potent activity against all clinical isolates, regardless of the KPC variant produced or the outer membrane permeability status. These findings were confirmed in wild-type and porin-deficient isogenic <i>E. coli</i> models, in which the combination of KPC variants and porin loss synergistically increased resistance to multiple β-lactams, while cefiderocol/xeruborbactam consistently restored susceptibility to wild-type levels. Comparative MIC analyses showed that xeruborbactam enhanced the activity of all β-lactam partners to a greater extent than taniborbactam. IC₅₀ determinations revealed a 17-fold to 73-fold greater inhibitory potency of xeruborbactam, which was maintained across structurally diverse KPC variants. Overall, cefiderocol/xeruborbactam exhibited potent activity against KPC-producing Enterobacterales, including isolates producing KPC variants associated with reduced susceptibility or resistance to ceftazidime/avibactam, cefiderocol, and cefepime/taniborbactam.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0089726"},"PeriodicalIF":4.2,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079623","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":"Anti-plasmodial activity of proteasome inhibitors against various <i>Plasmodium</i> species: a preclinical evaluation.","authors":"Nguyen Van Truong, Tuyet-Kha Nguyen, Nguyen Sy Thau, Thi-Thanh Hang Chu, Jin-Hee Han, Sung-Hun Na, Won-Sun Park, Wan-Joo Chun, Joo Hwan No, Feng Lu, Robert W Moon, Eun-Taek Han","doi":"10.1128/aac.00382-26","DOIUrl":"https://doi.org/10.1128/aac.00382-26","url":null,"abstract":"<p><p>The discovery of novel anti-malarial drugs has become urgent due to increasing drug resistance. Our previous work identified ONX-0914, which targets parasite proteolytic systems, as promising against <i>Plasmodium falciparum</i>. This study aims to further evaluate the antiplasmodial activity of ONX-0914 and related proteasome inhibitors (PIs) against various <i>Plasmodium</i> strains. The <i>in vitro</i> antimalarial activity of the inhibitors was evaluated against the <i>Plasmodium knowlesi</i> A1H1 strain and compared with that against the chloroquine (CQ)-sensitive <i>P. falciparum</i> 3D7 strain. Potent synergistic interactions between compounds and artemisinin (ART) were analyzed against PkA1H1 and ART-resistant PfDd2R539T(+) using an isobologram. To explore the mode of action, the disruption of the ubiquitin-proteasome system (UPS) in PkA1H1 and Pf3D7 was investigated. <i>In vivo</i> efficacy of ONX-0914 was further validated against CQ-resistant <i>Plasmodium yoelii</i>. PIs significantly inhibited PkA1H1 proliferation with low-nanomolar IC₅₀ values; ONX-0914 and LU-005i were more potent against PkA1H1 than Pf3D7, and effectively blocked multiple blood stages. Inhibition of parasite growth correlated with potent disruption of UPS at nanomolar concentrations (IC₅₀ < 50 nM). ONX-0914 demonstrated strong synergistic activity with ART and other PIs (∑FIC50 < 0.8). <i>In vivo</i>, ONX-0914 significantly suppressed <i>P. yoelii</i> infection, improving lifespan, with ⁓84% efficacy at an intraperitoneal (IP) dose of 20 mg/kg, and ⁓90% in combination with artemisinin at a dose of 10 mg/kg (IP). Further optimization of the structure and dosing regimen is able to enhance the therapeutic potential of PIs as potential antimalarial drug candidates.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0038226"},"PeriodicalIF":4.2,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079621","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 Phase I, randomized, double-blind, placebo-controlled, dose escalation study to evaluate the safety, tolerability, and pharmacokinetics of intravenous ertapenem and zidebactam in combination (WCK 6777) in healthy adult subjects.","authors":"T P Lodise, R Chavan, A Patel, R Yeole, S Bhagwat, M Patel, G A Saviolakis, M Kankam, K Gu, V Ghazaryan, A Jaunarajs, S R Fairfax, H Howell, R A Bonomo","doi":"10.1128/aac.00390-26","DOIUrl":"https://doi.org/10.1128/aac.00390-26","url":null,"abstract":"<p><p>WCK 6777 is a novel once-daily β-lactam enhancer combination comprising ertapenem (ERT) and zidebactam (ZID), designed to expand ERT activity against multidrug-resistant gram-negative Enterobacterales, including serine- and metallo-β-lactamase producers. This first-in-human, randomized, double-blind, placebo-controlled Phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of WCK 6777 and its individual components following once-daily intravenous administration for 7 days in healthy adults. In total, 54 participants were enrolled, of whom 52 received ERT alone (2 or 3 g), ZID alone (2 or 3 g), WCK 6777 (ERT + ZID at 1 + 1, 2 + 2, or 3 + 3 g), or placebo. Safety assessments included adverse events, clinical laboratory testing, vital signs, and electrocardiography. Plasma and urine PK of total and unbound ERT and ZID were characterized using noncompartmental methods. WCK 6777 was safe and well tolerated at all dose levels, with no deaths, serious adverse events, or treatment discontinuations. Adverse events were predominantly mild or moderate and were most commonly infusion-site reactions. Both ERT and ZID exhibited predictable, time-independent PK. Ertapenem exhibited a biphasic disposition with a terminal half-life supportive of once-daily dosing, whereas ZID displayed linear PK across the evaluated dose range. Plasma exposure, clearance, protein binding, and renal excretion were comparable between monotherapy and combination regimens, indicating no clinically meaningful PK interaction. Both drugs were eliminated predominantly unchanged in urine. In summary, WCK 6777 demonstrated a favorable safety profile and predictable PK following once-daily administration, supporting further clinical development, including evaluation in Phase II/III efficacy studies and potential application in outpatient parenteral antimicrobial therapy.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT05645757.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0039026"},"PeriodicalIF":4.2,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079602","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, safety, and tolerability of ceftibuten-ledaborbactam etzadroxil in participants with renal impairment.","authors":"Carlos Fernando de Oliveira, Kathryn Lowe, Penny Fatato, Thomas Marbury, Karine Litherland, Marc Engelhardt, Kamal A Hamed, Paul C McGovern","doi":"10.1128/aac.00860-26","DOIUrl":"10.1128/aac.00860-26","url":null,"abstract":"<p><p>Ledaborbactam etzadroxil is an orally bioavailable prodrug of ledaborbactam, a broad-spectrum β-lactamase inhibitor being developed in combination with ceftibuten for the treatment of complicated urinary tract infections caused by antibiotic-resistant pathogens. As both agents are primarily eliminated via renal excretion, dose adjustment may be required in patients with impaired renal function. This phase 1 study (NCT05488678) evaluated the pharmacokinetics and safety of ceftibuten and ledaborbactam etzadroxil in participants with normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease (ESRD) undergoing hemodialysis. Participants received a single dose of ceftibuten-ledaborbactam etzadroxil (600 mg/600 mg); those with ESRD received doses both before and after hemodialysis. Among 32 enrolled participants, the mean age was 62.2 years, and 81.3% were male. For both ceftibuten and ledaborbactam, decreasing renal function was associated with increased plasma exposure and reduced renal clearance (CLr). In participants with mild, moderate, or severe renal impairment, plasma exposure of ceftibuten increased 1.3-, 2.3-, and 3.7-fold, respectively, and ledaborbactam increased 1.5-, 1.9-, and 4.4-fold, respectively. Ceftibuten CLr decreased from 2.2 L/h in participants with normal function to 0.3 L/h in those with severe impairment, while ledaborbactam CLr decreased from 3.0 to 0.5 L/h. In participants with ESRD, both drugs were moderately removed (23% and 38% for ceftibuten and ledaborbactam, respectively) by hemodialysis. No deaths, serious adverse events, or treatment-related adverse events leading to study drug discontinuation were reported. These results indicate that dose adjustment of ceftibuten-ledaborbactam etzadroxil will be required for patients with reduced renal function.This study is registered with ClinicalTrials.gov as NCT05488678.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0086026"},"PeriodicalIF":4.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069387","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}