Antimicrobial Agents and Chemotherapy最新文献

{"title":"Contribution of RND superfamily multidrug efflux pumps AdeABC, AdeFGH, and AdeIJK to antimicrobial resistance and virulence factors in multidrug-resistant <i>Acinetobacter baumannii</i> AYE.","authors":"Lulin Xie, Junwei Li, Qin Peng, Xianqing Liu, Fei Lin, Xiaozhen Dai, Baodong Ling","doi":"10.1128/aac.01858-24","DOIUrl":"10.1128/aac.01858-24","url":null,"abstract":"<p><p><i>Acinetobacter baumannii</i> is a critical priority gram-negative bacterial species characterized by multidrug resistance. The latter is significantly attributable to the resistance-nodulation-cell division (RND) superfamily of tripartite multidrug efflux systems represented by AdeABC, AdeFGH, and AdeIJK. By constructing isogenic deletion mutants, this investigation assessed the impact of RND efflux pumps on planktonic and biofilm cell antimicrobial susceptibility as well as on biofilm formation and virulence factors in a multidrug-resistant reference strain, <i>A. baumannii</i> AYE. Inactivation of individual genes encoding the aforementioned three RND pumps or regulators (i.e., AYE△<i>adeA</i>, △<i>adeB</i>, △<i>adeC</i>, △<i>adeRS</i>, △<i>adeFGH</i>, and △<i>adeIJK</i> mutants) demonstrated that the three efflux pumps, particularly AdeB, contribute to resistance in both planktonic and biofilm cells to structurally unrelated anti-<i>A</i>. <i>baumannii</i> drugs, including carbapenems, fluoroquinolones, macrolides, polymyxins, and/or tetracyclines/tigecycline. The pump inactivation also altered other functions, changes in bacterial motility and adhesion, reduction of biofilm formation, and decreased expression of the genes related to biofilm formation and virulence factors (<i>abaI</i>, <i>bap, bfmR</i>, <i>csuE</i>, <i>ompA,</i> and <i>pgaA</i>, except for <i>abaR</i> whose expression was increased). The virulence assay measured through the survival rates of <i>A. baumannii</i>-infected <i>Galleria mellonella</i> revealed the relation between RND pumps (particularly AdeB) and pathogenicity. The findings together expand the understanding of specific <i>A. baumannii</i> RND pumps or components for their roles in resistance and virulence/pathogenicity in the presence of high-level multidrug resistance, highlighting the RND pumps as potential therapeutic intervention targets against <i>A. baumannii</i> infection.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0185824"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12217454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126171","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":"Plasma and intrapulmonary pharmacokinetics of cefepime and taniborbactam in healthy adult participants.","authors":"Keith A Rodvold, Mark H Gotfried, Philip Sabato, Tim Henkel, Paul C McGovern","doi":"10.1128/aac.00493-25","DOIUrl":"10.1128/aac.00493-25","url":null,"abstract":"<p><p>Cefepime-taniborbactam is being developed for the treatment of serious multidrug-resistant (MDR) Gram-negative bacterial infections. This study determined and compared plasma and epithelial lining fluid (ELF) concentrations of cefepime and taniborbactam in 30 healthy adult participants. The dosing regimen was 2 g cefepime/0.5 g taniborbactam administered as a 4 h intravenous infusion every 8 h for a total of six doses. Mean plasma and ELF concentration values with the four aspirates at each bronchoalveolar lavage (BAL) sampling time (1, 3, 4.25, 5, 6, and 8 h) were used to estimate the area under the concentration-time curve (AUC_0-8). The mean AUC_0-8 values of unbound plasma concentrations of cefepime and taniborbactam were 262.2 and 84.77 µg·h/mL, respectively. The drug penetration ratios of ELF to unbound plasma concentrations (DPR_ELF/plasma) were based on the AUC_0-8 values of six different BAL aspirate calculations: single aspirates (for the first, second, third, and fourth BAL sample) and pooled aspirates (BAL samples 2+3+4 and 1+2+3+4). The AUC_0-8 values for ELF for individual and pooled aspirates ranged from 51.62 to 97.86 µg·h/mL for cefepime and 13.14 to 21.69 µg·h/mL for taniborbactam. The DPR_ELF/plasma ranged from 0.197 to 0.373 for cefepime and 0.153 to 0.253 for taniborbactam and was dependent on which aspirate of recovered BAL fluid was used. The highest and lowest values of AUC_0-8 values for ELF and DPR_ELF/plasma for cefepime and taniborbactam were observed with aspirate 1 and aspirate 4, respectively. These results support further consideration of cefepime-taniborbactam as a potential treatment for bacterial pneumonia caused by susceptible MDR Gram-negative pathogens.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04951505.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0049325"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12217482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232973","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":"D-alanine synthesis and exogenous alanine affect the antimicrobial susceptibility of <i>Staphylococcus aureus</i>.","authors":"Yujin Suzuki, Miki Kawada-Matsuo, Vy Ton That Thuan, Mi Nguyen-Tra Le, Takemasa Sakaguchi, Hitoshi Komatsuzawa","doi":"10.1128/aac.01936-24","DOIUrl":"10.1128/aac.01936-24","url":null,"abstract":"<p><p>D-alanine is an important amino acid for peptidoglycan biosynthesis in <i>Staphylococcus aureus</i>. In addition, D-alanine is used for the modification of teichoic acids to weaken the net surface negative charge, leading to decreased susceptibility to cationic antimicrobial agents. D-alanine synthesis is dependent on only two enzymes. One is alanine racemase, encoded by the <i>alr1</i> gene, which reversibly converts L-alanine and D-alanine. The other is D-amino acid transaminase, encoded by the <i>dat</i> gene, which synthesizes D-amino acids from α-keto acids and other D-amino acids. In addition, the uptake of L- and D-alanine is dependent on the alanine transporter CycA. To reveal the relationship between D-alanine supply and antimicrobial susceptibility, we evaluated antimicrobial susceptibility in <i>alr1, dat,</i> and <i>cycA</i> inactivation mutants. These mutants, especially the Δ<i>alr1</i> and Δ<i>cycA</i> mutants, presented increased susceptibility to β-lactams, D-cycloserine, bacitracin, lysostaphin, and cationic antimicrobial agents such as aminoglycosides, nisin A, and daptomycin. The net negative charge of the cell surface increased in the Δ<i>alr1</i> and Δ<i>cycA</i> mutants. The changes in susceptibility to antimicrobial agents and cell surface charge were restored in their gene-complemented mutants. Furthermore, in an alanine-depleted medium, the MIC for oxacillin decreased significantly, and the MIC for gentamicin also decreased slightly. Clinical MRSA strains also showed significantly increased susceptibility to oxacillin in the alanine-depleted medium. These results indicate that D-alanine deficiency leads to impaired peptidoglycan and increased net surface negative charge, resulting in increased antimicrobial susceptibility.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0193624"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12217452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274093","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 pharmacokinetic analyses for telavancin using data from healthy subjects and patients with infections.","authors":"Scott A Van Wart, M Courtney Safir, Sujata M Bhavnani, Thomas P Lodise, Christopher M Rubino","doi":"10.1128/aac.01382-24","DOIUrl":"10.1128/aac.01382-24","url":null,"abstract":"<p><p>Telavancin is an intravenously administered lipoglycopeptide antibiotic active against clinically relevant gram-positive pathogens. In these analyses, a population pharmacokinetic (PK) model was constructed to describe the time course of telavancin in plasma and epithelial lining fluid (ELF) using data from healthy subjects and patients with complicated skin and skin-structure infections, hospital-acquired and ventilator-associated bacterial pneumonia, or uncomplicated bacteremia across Phases 1-4 of clinical development. Data from 1,205 individuals pooled from 21 studies contributed a total of 9,088 telavancin plasma concentrations. The final model for telavancin was a two-compartment model with zero-order intravenous input and linear elimination. Dialysis clearance was included as part of the base structural PK model; the relationship between telavancin clearance and creatinine clearance was included <i>a priori</i>. Body weight, age, and infection type were identified as statistically significant predictors of the interindividual variability (IIV) in total clearance. Body weight, age, and infection type were also identified as statistically significant predictors of IIV for the central and peripheral volumes of distribution. Only body weight was found to be a significant predictor of the IIV in distributional clearance. The model for ELF did not reveal any appreciable biases and determined the average free-drug ELF penetration ratio to be 73.0%. In summary, the population PK model characterized the time course of telavancin in both plasma and ELF robustly, captured the impact of clinically meaningful patient covariate effects, including removal of drug due to hemodialysis, and provided reliable individual <i>post hoc</i> estimates of exposure in subjects enrolled in the clinical studies.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0138224"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12217474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274094","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":"Two novel trimethoprim resistance genes, <i>dfra50</i> and <i>dfra51</i>, identified in phage-plasmids.","authors":"Kai Wang, Jikai Xu, Xiaowei Lu, Pan Yin, Li Chen, Ziwei Zhao, Alejandra Bravo, Mario Soberón, Jinshui Zheng, Ming Sun, Donghai Peng","doi":"10.1128/aac.01695-24","DOIUrl":"10.1128/aac.01695-24","url":null,"abstract":"<p><p>Phage-plasmids carry a significant burden of clinically relevant antibiotic resistance genes (ARGs). Intriguingly, the majority of these ARGs are found within plasmids with phage features, with a single exception residing in a phage genome with plasmid features. Therefore, we speculate that phage genomes with plasmid features, whose sequences are highly homologous to bacterial plasmids, may carry novel ARGs. We subsequently identified 46 such phage genomes by employing Hidden Markov models (HMMs) based on plasmid-specific protein profiles andbasic local alignment search tool (BLASTn) searches against the National Center for Biotechnology Information (NCBI) RefSeq Plasmid Database. Among them, six phages harbored seven ARGs identified through a lenient-threshold search strategy, of which only two had been previously reported. The remaining five ARGs were categorized as novel ARGs since their encoded proteins differed from known ARGs. Notably, half of the phages carried trimethoprim-resistant <i>dfrA</i>-like genes. Functional studies characterized these genes and demonstrated that the expression of two of these <i>dfrA</i> genes (<i>dfrA50</i> and <i>dfrA51</i>) can confer resistance to trimethoprim in <i>Escherichia coli</i>. Through genome analysis, we found that these phages with plasmid features likely contributed to the natural dissemination of these <i>dfrA</i> genes, as evidenced by their widespread presence in plasmids across various pathogenic bacteria. These findings underscore the importance of identifying and monitoring ARGs encoded by phage genomes with plasmid features that also function as plasmids in bacteria, aiming to proactively address the antibiotic resistance challenges posed by these phage-mediated dissemination events.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0169524"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12217456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274096","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":"Correction for Nelson et al., \"Pbp4 provides transpeptidase activity to the FtsW-PbpB peptidoglycan synthase to drive cephalosporin resistance in <i>Enterococcus faecalis</i>\".","authors":"Madison E Nelson, Jaime L Little, Christopher J Kristich","doi":"10.1128/aac.00594-25","DOIUrl":"10.1128/aac.00594-25","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0059425"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12217480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109114","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":"SAND: a comprehensive annotation of class D β-lactamases using structural alignment-based numbering.","authors":"Fedaa Attana, Soobin Kim, James Spencer, Bogdan I Iorga, Jean-Denis Docquier, Gian Maria Rossolini, Mariagrazia Perilli, Gianfranco Amicosante, Alejandro J Vila, Sergei B Vakulenko, Shahriar Mobashery, Patricia Bradford, Karen Bush, Sally R Partridge, Andrea M Hujer, Kristine M Hujer, Robert A Bonomo, Shozeb Haider","doi":"10.1128/aac.00150-25","DOIUrl":"10.1128/aac.00150-25","url":null,"abstract":"<p><p>Class D β-lactamases are a diverse group of enzymes that contribute to antibiotic resistance by inactivating β-lactam antibiotics. Examination of class D β-lactamases has evolved significantly over the years, with advancements in molecular biology and structural analysis providing deeper insights into their mechanisms of action and variation in specificity. However, one of the challenges in the field is the inconsistent residue numbering and secondary structure annotation across different studies, which complicates the comparison and interpretation of data. To address this, we propose SAND-a standardized naming system for both residues and secondary structure elements, based on a comprehensive structural alignment of all documented sequences and experimentally obtained crystal structures of class D β-lactamases. This unified framework will streamline cross-study comparisons and enhance data interpretation. Moreover, the standardized framework will enable AI-driven natural language processing (NLP) techniques to efficiently mine and compile relevant data from scientific literature, speeding up the discovery process and contributing to more rapid advancements in β-lactamase research.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0015025"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12217458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148894","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":"Synergistic combination of next-generation polymyxin MRX-8 and meropenem against carbapenem-resistant <i>A. baumannii</i>.","authors":"Xiaofen Liu, Xingyi Qu, Ruohao Zhang, Yuxin Zhang, Xingchen Bian, Yu-Wei Lin, Jing Zhang","doi":"10.1128/aac.01912-24","DOIUrl":"10.1128/aac.01912-24","url":null,"abstract":"<p><p>MRX-8 is a new next-generation polymyxin with potent antibacterial activity against carbapenem-resistant <i>Acinetobacter baumannii</i> (CRAB). This study evaluated the MRX-8 and meropenem combination and their dosing regimens against CRAB in clinics. Seven CRAB strains isolated from Huashan Hospital were tested. Two strains of AB21-3881 and AB21-3759 were selected for static time-kill and the Hollow Fiber Infection Model (HFIM). Adaptive resistance to MRX-8 was assessed via population analysis profiling (PAP) at 2 mg/L of MRX-8. Multilocus sequence typing identified all seven strains as ST2. Minimum inhibitory concentration values for MRX-8 ranged from 0.5 to 1 mg/L. Synergy was observed in six out of seven (85.7%) strains. The combination of 1 mg/L MRX-8 with 1 mg/L meropenem completely inhibited bacterial growth within 24 h for both selected strains. In HFIM, the combination of MRX-8 (0.75 mg/kg q8h continuous infusion) and meropenem (1 g q6h continuous infusion) achieved synergistic killing over 72 h for AB21-3759, while single treatment of MRX-8 (0.75 mg/kg q8h continuous infusion) achieved bactericidal effect (lower than the detect limitation) over 72 h. PAP analysis demonstrated that the combinational therapy could delay the emergence of adaptive resistance sub-populations by 12-24 h. The combination of MRX-8 and meropenem demonstrated synergistic bactericidal activity by checkerboard and static time-kill curves. Additionally, in HFIM, MRX-8 at 1 mg/kg q12h combined with meropenem at 2 g q12h, as well as MRX-8 at 0.75 mg/kg q8h continuous infusion combined with meropenem at 1 g q6h continuous infusion, achieved bacteriostatic killing at 72 h compared to the initial inoculum.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0191224"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12217483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148901","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 pre-post quasi-experimental study of antimicrobial stewardship exploring the impact of a multidisciplinary approach aimed at attaining an aggressive joint pharmacokinetic/pharmacodynamic target with ceftazidime/avibactam on treatment outcome of KPC-producing <i>Klebsiella pneumoniae</i> infections and on ceftazidime/avibactam resistance development.","authors":"Milo Gatti, Matteo Rinaldi, Pier Giorgio Cojutti, Cecilia Bonazzetti, Antonio Siniscalchi, Tommaso Tonetti, Simone Ambretti, Sara Tedeschi, Maddalena Giannella, Pierluigi Viale, Federico Pea","doi":"10.1128/aac.00488-25","DOIUrl":"10.1128/aac.00488-25","url":null,"abstract":"<p><p>To assess the impact of a multidisciplinary approach aimed at attaining aggressive joint pharmacokinetic/pharmacodynamic (PK/PD) target with ceftazidime/avibactam on treatment outcome of KPC-<i>Klebsiella pneumoniae</i> (Kp) infections and prevention of ceftazidime/avibactam resistance development, a pre-post quasi-experimental study on adult patients with documented KPC-Kp who were treated with ceftazidime/avibactam according to a multidisciplinary approach in the period 1 March 2021-31 October 2024 and patients receiving standard management with ceftazidime/avibactam in the period 1 January 2018-28 February 2021 was performed. Multivariate analysis was performed to identify variables associated with microbiological failure and 90-day resistance development to ceftazidime/avibactam in both pre- and post-intervention phases. A total of 116 and 102 patients in pre- and post-intervention phases were included. A significantly lower microbiological eradication rate (53.0% vs. 81.0%; <i>P</i> < 0.001), a lower clinical cure rate (48.3% vs. 70.6%; <i>P</i> < 0.001), and a higher rate of 90-day resistance development (15.5% vs. 5.9%; <i>P</i> = 0.02) were found in the pre-intervention phase. Continuous renal replacement therapy (odds ratio [OR] 5.20; 95% confidence interval [CI] 1.21-22.34) and a ceftazidime/avibactam MIC value ≥ 4 mg/L (OR 3.08; 95% CI 1.10-8.64) emerged as independent predictors of microbiological failure in the pre-intervention phase. Conversely, attaining aggressive joint PK/PD target (OR 0.03; 95% CI 0.005-0.20) and bloodstream infections (OR 0.09; 95% CI 0.02-0.53) resulted in protection against microbiological failure in the post-intervention phase. Attaining aggressive joint PK/PD targets resulted in protection against 90-day resistance development in the post-intervention phase (OR 0.07; 95% CI 0.01-0.69). Implementing a multidisciplinary approach for maximizing the attainment of aggressive joint PK/PD targets of ceftazidime/avibactam could represent an effective strategy for preventing resistance development to ceftazidime/avibactam in KPC-Kp infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0048825"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12217479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232962","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":"Pharmacokinetics of nikkomycin Z following multiple doses in healthy subjects.","authors":"David E Nix, Susan E Hoover, Nathan J Hanan, John Galgiani","doi":"10.1128/aac.00395-25","DOIUrl":"10.1128/aac.00395-25","url":null,"abstract":"<p><p>Nikkomycin Z is an investigational antifungal agent that inhibits chitin synthesis. The drug shows promise against endemic fungi such as <i>Coccidioides</i> spp. The purpose of this study was to determine the pharmacokinetics and safety when administered as multiple, ascending doses in healthy subjects. Healthy adult volunteers received nikkomycin Z in oral doses ranging from 250 mg twice daily to 750 mg three times a day for 14 days. An intensive pharmacokinetic study was conducted after the first dose (day 1) and after the last dose (day 14). Subjects were also monitored for safety and tolerance but were not confined to the facility continuously. Doses were tracked by self-reporting and were observed prior to intensive pharmacokinetic studies. On day 14, the mean (sd) maximal concentration ranged from 3.70 (1.08) to 6.89 (1.59) mg/L, and mean time of maximal concentration ranged from 2.3 to 3.0 h. The mean area under the time curve from time 0 to end of the dosing interval (8 or 12 h) was 17.3 (5.2) mg h/L for 250 mg twice daily, 28.5 (9.5) for 500 mg twice daily, 34.5 (10.9) for 750 mg twice daily, and 35.6 (8.4) for 750 mg thrice daily. The mean half-life ranged from 1.94 to 2.18 h. Bioavailability was less than proportional to dose for the 750 mg doses. Nikkomycin Z was well tolerated, and the study was completed without any serious safety concerns. This study supports continued development of nikkomycin Z as a potential therapeutic for the treatment of coccidioidomycosis.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0039525"},"PeriodicalIF":4.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12217460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232963","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}