Antimicrobial Agents and Chemotherapy最新文献

{"title":"Cefazolin population pharmacokinetics in children undergoing maintenance hemodialysis for kidney failure.","authors":"Romain Berthaud, Saïk Urien, Saoussen Krid, Frantz Foissac, Mehdi Oualha, Michaël Thy, Olivia Boyer, Agathe Béranger, Déborah Hirt, Sihem Benaboud, Jean-Marc Tréluyer, Naïm Bouazza","doi":"10.1128/aac.00451-25","DOIUrl":"https://doi.org/10.1128/aac.00451-25","url":null,"abstract":"<p><p>We aimed to develop a population pharmacokinetic model of cefazolin in children undergoing maintenance hemodialysis for kidney failure and simulate dosing regimens to optimize patients' exposure. Cefazolin plasma concentrations were quantified using high-performance liquid chromatography. A non-linear mixed-effect modeling approach was used to investigate cefazolin pharmacokinetics. Optimal dosing regimens were determined using Monte Carlo simulations targeting 100% of the time a free plasma concentration four times above the minimum inhibitory concentration (MIC) and total plasma concentration less than 80 mg/L (100% fT > 4 × MIC and <i>C</i> < 80 mg/L). Eighty-three samples were analyzed from six patients aged 1.3-14.6 years and weighing 11.4-51 kg. A one-compartment model with first-order elimination best fitted the data, with a significant between-subject variability (BSV). Body weight (BW), using the allometric rule, was a significant predictor of residual elimination clearance (CL) and volume of distribution (Vd), while dialysis membrane surface area (DMSA) explained almost all the BSV on dialysis clearance (CLdial). The parameter relationships were Vd_<i>i</i>(L) = 14.6 × (BW<i>_i</i>/70), CL_i(L/h) = 0.186 × (BW<i>_i</i>/70)^0.75, CLdial_<i>i</i>(L/h)=1.98 × (DMSA<i>_i</i>/1)^1.26, CLtot_i = CL<i>_i +</i> CLdial_DMSA<i>_i</i>, where the subscript <i>i</i> denotes the <i>i</i>^th patient's covariate value. Dosing regimens were simulated for six CL ranges, targeting two concentration intervals: 40-80 mg/L and 20-80 mg/L for MIC of 2 and 1 mg/L, respectively. In children on maintenance hemodialysis for kidney failure, due to the persistence of a large unexplained BSV on CL that substantially affects them, optimal dosing regimen would not be accurately determined a priori and should be individually determined using therapeutic drug monitoring, taking BW, DMSA, and CL into account.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT02539407.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0045125"},"PeriodicalIF":4.5,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205460","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":"Prevalence of resistance markers of artemisinin, partner drugs, and sulfadoxine-pyrimethamine in Nanyumbu and Masasi Districts, Tanzania between 2020 and 2021.","authors":"Richard O Mwaiswelo, Bruno P Mmbando, Frank Chacky, Fabrizio Molteni, Ally Mohamed, Samwel Lazaro, Bushukatale Samuel, Cristina V Ariani, Sonia Gonçalves, Eleanor Drury, Billy Ngasala","doi":"10.1128/aac.01751-24","DOIUrl":"10.1128/aac.01751-24","url":null,"abstract":"<p><p>Regular monitoring of the emergence and spread of <i>Plasmodium falciparum</i> markers of resistance against artemisinin, partner drugs, sulfadoxine, and pyrimethamine is important for the treatment and prevention of malaria in Tanzania. Blood samples were collected from febrile and non-febrile children aged 3 to 59 months in Masasi and Nanyumbu Districts between 2020 and 2021. The samples were subjected to molecular analysis for markers of artemisinin, partner drugs, sulfadoxine, and pyrimethamine resistance, including <i>Plasmodium falciparum</i> kelch (<i>Pfk</i>) 13 gene, <i>P. falciparum</i> chloroquine resistance transporter gene (<i>Pfcrt</i>), <i>P. falciparum</i> multidrug resistance gene (<i>Pfmdr</i>) 1, <i>P. falciparum</i> dihydrofolate reductase (<i>Pfdhfr</i>), and <i>P. falciparum</i> dihydropteroate synthase (<i>Pfdhps</i>). A total of 531 blood samples were involved in the analysis. None of the <i>P. falciparum</i> isolates analyzed for <i>Pfk13</i> carried any of the validated markers of artemisinin resistance. <i>Pfcrt</i> CVMNK wild-type haplotype occurred in 88.9% (271/305) of the parasites, and the mutant CVIET haplotype occurred only in 0.7% (2/305). Conversely, the majority of the parasites (24.2% [48/198]) were carrying <i>Pfmdr1</i> NFD haplotype, followed by the wild-type haplotype NYD (19.1% (39/198), and the rest were mixed infections. Quintuple mutation <b><u>IRN</u></b>I-S<b><u>GE</u></b>AA occurred in 54.4% (62/114), and sextuple mutation <b><u>IRN</u></b>I-<b><u>F</u></b>AK<b><u>GS</u></b> occurred only in 0.9% (1/114) of the parasites. No parasite carried any of the validated markers of artemisinin resistance; however, the prevalence of <i>Pfcrt</i> and <i>Pfmdr1</i> resistance markers against the partner drugs reached the saturation point. Sextuple <i>Pfdhfr-Pfdhps</i> mutations occurred only in one patient; therefore, SP remains efficacious for IPTp in the Districts.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0175124"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039004","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":"Mechanistic blockade of <i>Pseudomonas aeruginosa</i> type III secretion by a monoclonal antibody targeting the pore size-determining domain of PcrV.","authors":"Yu Zhang, Shiyu Guo, Liwen Jiang, Siqi Wang, Weitong Hou, Xiran Qiu, Hui Shen, Maomao An","doi":"10.1128/aac.00405-25","DOIUrl":"10.1128/aac.00405-25","url":null,"abstract":"<p><p><i>Pseudomonas aeruginosa</i> bloodstream infections carry mortality rates exceeding 60%, with escalating antibiotic resistance dramatically limiting therapeutic options. The type III secretion system (T3SS), a virulence apparatus delivering cytotoxic effectors via PcrV-dependent translocation pores, represents a therapeutic target. Here, we developed a monoclonal antibody (5C8) targeting the central domain (H106-D173) of PcrV, which regulates translocation pore size. 5C8 demonstrated sub-nanomolar affinity (KD = 0.32 nM) via biolayer interferometry and broad neutralization efficacy against clinical isolates (IC₅₀: 0.32-1.47 μg/mL). In murine bloodstream infection models, 5C8 conferred improved survival against cytotoxic (<i>exoU⁺</i>) and invasive (<i>exoS⁺</i>) strains (<i>P</i> < 0.01 vs controls), reducing bacterial loads in lungs/kidneys by 1.5-log₁₀ colony-forming unit (<i>P</i> < 0.01) and suppressing interleukin-6 levels by 60-82% (<i>P</i> < 0.01). Mechanistic studies revealed 5C8's dual action: blocking effector release (ExoU/ExoT reduced by 41-88% via liquid chromatography-mass spectrometry) and constricting T3SS pores below 1.2 nm (carbohydrate exclusion assay). Molecular docking identified D125/K129/Y145 as critical binding residues, validated by alanine scanning and mutant construction. Humanized Hu5C8 retained potency (KD = 0.55 nM) with extended half-life (t_1/2 = 91.26 h) through Fc receptor engineering. As an inhibitor targeting the pore size-determining domain of PcrV, 5C8 disrupts virulence through a novel dual mechanism, providing a paradigm-shifting strategy against multidrug-resistant <i>P. aeruginosa</i>, bridging a critical gap in sepsis management.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0040525"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871022","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":"Microbiological evidence for the trisubstituted benzimidazoles targeting MmpL3 in <i>Mycobacterium tuberculosis</i>.","authors":"Mengyun Zhang, Renee Allen, Lauren Ames, Curtis A Engelhart, Diana Quach, Xiaoying Lv, Genhui Xiao, Heng Wang, Jinglan Wang, Liangliang Zhou, Miaomiao Pan, Joseph Sugie, Joe Pogliano, Dirk Schnappinger, Tanya Parish, Shawn Chen","doi":"10.1128/aac.00368-25","DOIUrl":"10.1128/aac.00368-25","url":null,"abstract":"<p><p>New anti-tuberculosis (TB) drugs with novel modes of action are in great demand due to the complex treatment regimens as well as the rising number of multidrug-resistant TB cases. We recently re-evaluated a few 2,5,6-trisubstituted benzimidazole derivatives (SBZ) previously demonstrated to have potent antitubercular activity. These compounds displayed favorable MICs and significantly reduced bacterial counts in an acute mouse infection model. Although this antitubercular lead series was initially reported to inhibit mycobacterial cell division, our findings suggest that its primary activity likely involves other cellular targets. By using bacterial cytological profiling, we observed that SBZ-treated <i>Mycobacterium tuberculosis</i> cells exhibit cell wall-damaging phenotypes resembling those caused by known cell wall biosynthesis inhibitors, such as AU1235 and SQ109, that mostly target the membrane protein large 3 (MmpL3). Whole-cell assays further supported the findings by showing activation of the <i>iniBAC</i> operon and accumulation of intracellular ATP. The antitubercular activity of SBZs was tested against engineered mycobacterial strains that have the transcriptionally regulated <i>mmpL3</i> gene expression, confirming that SBZs engage the MmpL3 target in the cell. Strains with mutations in <i>mmpL3</i> exhibited either low- or high-level resistance to the SBZs. A molecule docking model is proposed, based on a high-resolution crystal structure of MmpL3, which could be useful in reconciling the inhibition mechanism and suggesting a further development of MmpL3 inhibitor starting with the SBZ scaffold.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0036825"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871023","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":"Genetic analysis of common triazole resistance mechanisms in a collection of <i>Aspergillus lentulus</i> clinical isolates from the United States.","authors":"Adela Martin-Vicente, Ashley V Nywening, Jinhong Xie, Harrison I Thorn, Xabier Guruceaga, Jarrod R Fortwendel","doi":"10.1128/aac.00690-25","DOIUrl":"10.1128/aac.00690-25","url":null,"abstract":"<p><p><i>Aspergillus fumigatus</i> continues to be the leading cause of invasive aspergillosis. However, the number of cases by drug-resistant cryptic species has increased in recent years. <i>Aspergillus lentulus</i> is a sibling species of <i>Aspergillus</i> section <i>Fumigati</i> that can only be distinguished from <i>A. fumigatus</i> by molecular methods. The clinical importance of this species resides in its low susceptibility to triazoles and intrinsic resistance to amphotericin B, making invasive aspergillosis treatments extremely challenging and producing high mortality rates. In this study, we investigate known molecular mechanisms important for triazole resistance in <i>A. fumigatus</i> in a collection of 25 clinical <i>A. lentulus</i> isolates from the United States. Using CRISPR-Cas9 gene editing technology, we performed <i>cyp51A</i> and <i>hmg1</i> allele replacements between susceptible and resistant isolates. Phenotypic characterization of the resulting mutants, together with mRNA expression analyzes of <i>cyp51A</i>, <i>cyp51B,</i> and the putative ABC efflux pump, <i>abcC</i>, suggests that triazole resistance in our <i>A. lentulus</i> isolates is independent of the mechanisms studied.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0069025"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038939","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":"Continuous or extended vs intermittent infusions of beta-lactam antibiotics in ICU patients with pneumonia: a systematic review and meta-analysis of randomized controlled trials.","authors":"Yixuan Li, Jason A Roberts, Mohd H Abdul-Aziz, Fekade B Sime","doi":"10.1128/aac.00732-25","DOIUrl":"10.1128/aac.00732-25","url":null,"abstract":"<p><p>This systematic review and meta-analysis of randomized controlled trials (RCTs) of intensive care unit (ICU) patients with pneumonia was conducted to compare the clinical outcomes of beta-lactam antibiotics when administered by prolonged infusion vs intermittent infusion. The systematic search was conducted in Medline (via PubMed), CINAHL, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. The outcomes were mortality, clinical cure rate, microbiological cure rate, adverse events, and ICU length of stay. The pooled risk ratios or mean differences were estimated by the fixed or random effect methods according to heterogeneity statistics. Twelve eligible RCTs were included in the meta-analysis. ICU length of stay was lower in the prolonged infusion patients compared with intermittent infusion. However, compared to intermittent infusion, the prolonged infusion, both continuous and extended infusion, of beta-lactam antibiotics was not associated with statistically significant improvements in mortality, clinical cure rate, microbiological cure rate, and rate of adverse events. For the treatment of ICU patients with pneumonia, prolonged infusion was associated with a shorter ICU length of stay. Multicenter RCTs with large sample sizes of ICU patients with pneumonia are needed to better assess other important endpoints.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0073225"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940047","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":"Efficacy and <i>in vitro</i> activity of gepotidacin against bacterial uropathogens, including drug-resistant phenotypes, in females with uncomplicated urinary tract infections: results from two global, pivotal, phase 3 trials (EAGLE-2 and EAGLE-3).","authors":"Nicole E Scangarella-Oman, Deborah L Butler, John Breton, Derrek Brown, Cara Kasapidis, Helen Millns, Chun Huang, Caroline R Perry, Amanda J Sheets, Jeremy Dennison, Salim Janmohamed","doi":"10.1128/aac.01640-24","DOIUrl":"10.1128/aac.01640-24","url":null,"abstract":"<p><p>Two recent Phase 3 trials demonstrated the efficacy of gepotidacin compared with nitrofurantoin to treat uncomplicated urinary tract infections (uUTIs) in females. Pretreatment urine specimens were obtained from all participants. Based on pooled trial data (treatment groups combined), central laboratory culture results identified 1,421 (45%) participants with ≥1 baseline qualifying (≥10⁵ CFU/mL) uropathogen (i.e., pooled microbiological Intent-to-Treat population). <i>Escherichia coli</i>, <i>Klebsiella pneumoniae</i>, and <i>Proteus mirabilis</i> were the most common qualifying uropathogens. Among 1,159 <i>E. coli</i> isolates, 28%, 28%, 15%, and 28% were fluoroquinolone resistant (FQ-R), trimethoprim-sulfamethoxazole resistant (SXT-R), extended-spectrum β-lactamase positive (ESBL+), and multidrug resistant (MDR), respectively. For 114 <i>K</i>. <i>pneumoniae</i> isolates, 25%, 23%, 16%, and 16% were nitrofurantoin resistant, SXT-R, FQ-R, and ESBL+, respectively. Of 67 <i>P</i>. <i>mirabilis</i> isolates, 25%, 21%, and 31% were SXT-R, FQ-R, and MDR, respectively. Gepotidacin MIC₉₀ values against all qualifying uropathogens and drug-resistant phenotypes ranged from 0.25 to 32 µg/mL, with no isolates of Enterobacterales, <i>Staphylococcus saprophyticus</i>, or <i>Enterococcus faecalis</i> considered resistant to gepotidacin. For all uropathogen drug-resistant phenotypes, gepotidacin MIC₉₀ values were similar (i.e., lower, equal to, or 1-dilution higher) compared with the MIC₉₀ of the overall species. Gepotidacin's efficacy, based on therapeutic, clinical, and microbiological success rates, was generally consistent across phenotypic subgroups of <i>E. coli</i>, <i>K. pneumoniae</i>, and <i>P. mirabilis</i>. This pooled analysis represents a robust, contemporary, clinically relevant, and unbiased (i.e., baseline urine specimens obtained from all enrolled participants regardless of uUTI history) collection of data from community-acquired uUTIs in females.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04020341 and NCT04187144.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0164024"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022800","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":"Phase 1, randomized, double-blind, placebo-controlled, ascending single- and multiple-dose study of the safety, tolerability, and pharmacokinetics of intravenous xeruborbactam (QPX7728) in healthy adult subjects.","authors":"María Patricia Hernández-Mitre, Steven C Wallis, Jeffery S Loutit, David C Griffith, Jason A Roberts","doi":"10.1128/aac.00784-25","DOIUrl":"10.1128/aac.00784-25","url":null,"abstract":"<p><p>The objective of this First-in-Human Phase 1, double-blind, randomized, placebo-controlled study was to assess the pharmacokinetics (PK), safety, and tolerability of the dual targeting beta-lactamase inhibitor xeruborbactam (QPX7728) in healthy adults. The study included single-ascending (SAD) and multiple-ascending dose (MAD) cohorts. Subjects received intravenous xeruborbactam at doses ranging from 250 to 2,000 mg. PK parameters of total and unbound xeruborbactam were derived from plasma, ultrafiltrate, and urine samples. Adverse events (AEs) were monitored and assessed throughout the study. Fifty-two subjects participated (39 xeruborbactam and 13 placebo). Following single doses, total and unbound xeruborbactam exhibited dose-dependent increases in exposure parameters (<i>C</i>_max, AUC_0-24, and AUC_0-INF). Mean terminal half-life ranged from 26.8 to 32.0 h for total xeruborbactam, and from 20.7 to 22.4 h for unbound xeruborbactam. The mean fraction of the administered dose excreted in the urine ranged from 82.9% to 85.0% after single doses, and from 71.5% to 81.2% after multiple doses. After repeated 8-hourly dosing in MAD cohorts 7 and 8, the mean accumulation ratios for total xeruborbactam were 5.0 and 6.1. Plasma protein binding showed a concentration-dependent trend, with increased unbound xeruborbactam concentrations at higher doses. AEs were not different between xeruborbactam and placebo participants and included headache, vascular access site bruising and pain, and self-resolving mild increases in alanine transaminases. No severe or serious AEs were observed. Xeruborbactam was primarily eliminated renally. Dose proportionality was only observed for unbound xeruborbactam. Significant accumulation was noted with 8-hourly dosing. Xeruborbactam at doses up to 1,000 mg daily for 7-10 days was well tolerated, with no serious or life-threatening AEs. Xeruborbactam was primarily eliminated renally. Dose proportionality was only observed for unbound xeruborbactam. Significant accumulation was noted with 8-hourly dosing. Xeruborbactam at doses up to 1,000 mg daily for 7-10 days was well tolerated, with no serious or life-threatening AEs.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0078425"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063384","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":"Piperacillin reaches high concentrations in bile and target tissues of the biliary system: an experimental study in pigs.","authors":"Louise L Pontoppidan, Mats Bue, Kim C Houlind, Anders R Knudsen, Jan B Pedersen, Magnus A Hvistendahl, Pelle Hanberg","doi":"10.1128/aac.00792-25","DOIUrl":"10.1128/aac.00792-25","url":null,"abstract":"<p><p>The antibiotic combination of piperacillin/tazobactam (TZP) is commonly utilized for preventing and treating infections in the biliary system, with piperacillin being the primary agent. Its effectiveness is closely related to the time with concentrations above the minimal inhibitory concentration (<i>T</i> > MIC) of the bacteria involved. The most frequently encountered bacteria associated with biliary system infections present with clinical breakpoint MIC values of 8 and 16 µg/mL. This porcine study aimed to apply microdialysis to assess target site piperacillin <i>T</i> > MIC 8, 16, and 32 (4× MIC 8) µg/mL in the biliary system. In eight healthy pigs (Danish Landrace breed, weight 78-82 kg), five microdialysis catheters were placed for sampling of piperacillin concentrations in the liver, the wall of the gallbladder, the bile in the gallbladder, the wall of the common bile duct (CBD), and the bile in the CBD. A bolus of TZP 4/0.5 g was administered intravenously, and microdialysates and blood samples were collected during an 8 h period. Ultrahigh performance liquid chromatography (UHPLC) was used to quantify the piperacillin concentrations. The mean <i>T</i> > MIC (%T > MIC) varied from 345 to 446 min (77%-99%), 261-446 min (58%-99%), and 200-444 min (42%-99%) for the MIC targets of 8, 16, and 32 µg/mL, respectively. The pharmacokinetic parameters in the bile were found to be different compared to the remaining compartments with higher AUC_0-8h and <i>C</i>_max values and longer <i>T</i>_1/2. Piperacillin displayed prolonged <i>T</i> > MIC in bile compared to plasma and the target tissues of the biliary system, approaching 100%<i>T</i> > MIC for the MIC targets of 8, 16, and 32 µg/mL.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0079225"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871046","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":"Population pharmacokinetic analysis of letermovir in adult hematopoietic cell transplant recipients.","authors":"Léna Royston, Carla Kunz, David Tonoli, Pierre Lescuyer, Dionysios Neofytos, Verena Gotta","doi":"10.1128/aac.00697-25","DOIUrl":"10.1128/aac.00697-25","url":null,"abstract":"<p><p>We analyzed previously reported oral letermovir plasma concentration measurements from 40 allogeneic hematopoietic cell transplant (HCT) recipients using model-based pharmacometrics analysis. This analysis highlighted that the industry-sponsored phase III study model significantly over-predicted observed letermovir concentrations. Covariates associated with increased oral clearance (CL/F), possibly contributing to this observation, included: higher weight, younger age, and early use after HCT. The clinical significance and mechanistic explanation of relatively lower real-world exposure remains to be elucidated.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0069725"},"PeriodicalIF":4.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940113","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}