Antimicrobial Agents and Chemotherapy最新文献

{"title":"<i>grdA</i> on different plasmids and chromosomes of <i>Salmonella enterica</i>.","authors":"Zhiqiu Yin, Xiaoyan Tian, Zhanpeng Yu, Mujie Zhang, Baozhu Chen, Yanling Zhang, Liang Peng","doi":"10.1128/aac.00669-25","DOIUrl":"https://doi.org/10.1128/aac.00669-25","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0066925"},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111909","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":"Molecular and pharmacodynamic insights into β-lactam therapy for high-inoculum <i>Enterobacter cloacae</i> complex infections.","authors":"Ashlan J Kunz Coyne, Rachel Gray, Elizabeth May, Hunter Curry, Nicole Slain, Chris Delcher, Eugene Shin","doi":"10.1128/aac.01170-25","DOIUrl":"https://doi.org/10.1128/aac.01170-25","url":null,"abstract":"<p><p>High-inoculum <i>Enterobacter cloacae</i> complex (ECC) infections challenge β-lactam therapy due to β-lactamase-mediated resistance and the inoculum effect, where high bacterial densities amplify resistance and worsen outcomes. We evaluated the pharmacodynamic efficacy of cefepime, meropenem, ertapenem, meropenem-vaborbactam, and ceftazidime-avibactam against three high-inoculum (10⁹ colony-forming unit [CFU]/g) ECC isolates (0008, 0032, and 0060) harboring diverse β-lactamases using a 96 h simulated endocardial vegetation (SEV) model with humanized exposures. Bactericidal activity, resistance emergence, and β-lactamase expression were assessed. Cefepime failed in all isolates, with SEV growth from +0.4 to +1.6 log₁₀ CFU/g and minimum inhibitory concentrations (MICs) increasing from 2-8 µg/mL to >64  µg/mL in 0008, 0032, and 0060, coinciding with AmpC β-lactamase (ACT) induction up to 16.1-fold (0032). In 0060, cefepime failed, whereas meropenem displayed infusion-dependent efficacy: the 3 h infusion achieved bactericidal killing (-4.6 log₁₀ CFU/g), while the 30 min infusion produced partial killing (-2.9 log₁₀ CFU/g). Meropenem failed in 0032 (+1.1 log₁₀ CFU/g), with ACT-16 induction reaching 14.6-fold. Ertapenem produced initial bactericidal activity in 0060 (-3.2 log₁₀ CFU/g) but regrowth to -1.9 log₁₀ CFU/g by 96 h, accompanied by ACT-89 expression rising 26-fold. Meropenem-vaborbactam was bactericidal in 0008 (-4.6 log₁₀ CFU/g) and 0032 (-3.6 log₁₀ CFU/g) with stable MICs and minimal β-lactamase induction. Ceftazidime-avibactam achieved bactericidal activity in 0008 (-4.9 log₁₀ CFU/g) but only bacteriostatic activity in 0032 (-1.2 log₁₀ CFU/g), with modest KPC-3 and ACT-16 upregulation (~1.7- to 2.3-fold). β-Lactamase diversity and inoculum effects limit β-lactam efficacy in high-inoculum ECC infections. Meropenem-vaborbactam showed consistent activity, and prolonged meropenem infusion benefited select isolates. Variable ceftazidime-avibactam efficacy reinforces aligning β-lactam selection with underlying β-lactamase mechanisms.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0117025"},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111855","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":"Comparison of different colistin sulfate regimens for carbapenem-resistant gram-negative bacteria pneumonia in neurocritical care patients: a retrospective cohort study.","authors":"Qian Zeng, Huawei Huang, Jiaqi Lu, Lei Wu, Shaolan Zhang, Jingwei Zhao, Guangqiang Chen, Hongliang Li, Guangzhi Shi","doi":"10.1128/aac.00644-25","DOIUrl":"https://doi.org/10.1128/aac.00644-25","url":null,"abstract":"<p><p>Nosocomial infection caused by carbapenem-resistant gram-negative bacteria (CR-GNB) is a common problem in neurocritical care patients. Clinical evidence suggests that polymyxins have benefits for CR-GNB pneumonia. This study compared the efficacy and safety of different colistin sulfate regimens in CR-GNB pneumonia. Among 133 neurocritical care patients with CR-GNB pneumonia in the intensive care unit (ICU), 24 received nebulized colistin sulfate alone (NC group); 38 received intravenous colistin sulfate alone (IV group); and 71 received nebulized plus intravenous colistin sulfate (NCIV group). After inverse probability of treatment weighting (IPTW), clinical failure rates on days 7 and 14 were significantly higher in the IV group than in the NC group (38.3% vs. 20.5%, <i>P</i> = 0.017 and 32.1% vs. 15.3%, <i>P</i> = 0.004, respectively) and the NCIV group (38.3% vs. 24.7%, <i>P</i> = 0.023 and 32.1% vs. 14.2%, <i>P</i> = 0.015, respectively). Moreover, the IV group also reported a lower microbiological eradication rate on day 14 (<i>P</i> = 0.031) and longer ICU (<i>P</i> = 0.020) and hospital stays (<i>P</i> = 0.037) than the NCIV group. No significant difference in mortality risk and nephrotoxicity among the groups. In multivariable analysis, intravenous colistin sulfate was an independent factor associated with higher clinical failure on day 14 (adjusted odds ratio = 5.92, 95% CI = 1.14-30.84, <i>P</i> = 0.035). Our study suggested that nebulized colistin sulfate with concurrent intravenous administration may be an effective and safe option for CR-GNB pneumonia.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0064425"},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111874","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":"Evaluation of <i>in vitro</i> efficacy of aztreonam-nacubactam and cefepime-nacubactam against clinical isolates of <i>Stenotrophomonas maltophilia</i>.","authors":"Wataru Aoki, Yoshifumi Uwamino, Hiroaki Kubota, Yuka Kamoshita, Rika Inose, Mika Nagata, Ho Namkoong, Hiromichi Matsushita","doi":"10.1128/aac.00755-25","DOIUrl":"https://doi.org/10.1128/aac.00755-25","url":null,"abstract":"<p><p>We evaluated the <i>in vitro</i> activity of aztreonam-nacubactam (ATM-NAC) and cefepime-nacubactam (FEP-NAC) against 53 clinical isolates of <i>Stenotrophomonas maltophilia</i> from blood cultures. Minimum inhibitory concentrations (MICs) were determined via broth microdilution. While ATM-NAC showed more significant MIC reduction, FEP-NAC also remarkably decreased MICs, despite cefepime being a substrate for L1 β-lactamase. These findings suggest the potential of β-lactam-NAC combinations as promising alternatives, warranting further <i>in vivo</i> studies to confirm clinical applicability.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0075525"},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111893","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 of sulbactam-durlobactam in patients with <i>Acinetobacter baumannii</i> ventriculitis: a report of two cases.","authors":"Nazanin Pouya, Natalie A Finch, Alejandro Granillo, Adarsh Bhimraj, Vincent H Tam, William R Miller","doi":"10.1128/aac.00674-25","DOIUrl":"https://doi.org/10.1128/aac.00674-25","url":null,"abstract":"<p><p>Two adult patients with ventriculitis due to <i>Acinetobacter baumannii</i> were treated with intravenous sulbactam-durlobactam as a part of a combination regimen. Penetration into the central nervous system was estimated (by cerebrospinal fluid [CSF]/serum area under the curve [AUC] ratios at steady state) for sulbactam (0.47-0.64) and durlobactam (0.27-0.3), respectively. In view of mostly constant CSF concentrations, single CSF levels at steady state may offer a more convenient and clinically applicable approach for monitoring therapy.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0067425"},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111877","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":"Targeting <i>Pseudomonas aeruginosa</i> resistance at the exposure frontier: a population PK/PD blueprint for ceftolozane/tazobactam continuous infusion.","authors":"Pier Giorgio Cojutti, Manjunath P Pai, Milo Gatti, Matteo Rinaldi, Tommaso Tonetti, Antonio Siniscalchi, Pierluigi Viale, Federico Pea","doi":"10.1128/aac.01042-25","DOIUrl":"https://doi.org/10.1128/aac.01042-25","url":null,"abstract":"<p><p>Ceftolozane/tazobactam is a key antibiotic for <i>Pseudomonas aeruginosa</i> infections. Our objective was to determine whether continuous infusion (CI) of ceftolozane/tazobactam can achieve aggressive pharmacokinetic/pharmacodynamic (PK/PD) targets that suppress resistance and improve outcomes in severe <i>Pseudomonas aeruginosa</i> infections. A retrospective analysis of adult patients receiving CI ceftolozane/tazobactam and therapeutic drug monitoring (TDM) of both compounds was performed. Population PK/PD modeling identified the most accurate method for estimating ceftolozane/tazobactam clearance based on kidney function and Monte Carlo simulations investigated the relationship between various CI dosing regimens and aggressive PK/PD target attainment of ceftolozane/tazobactam. The 2021 non-race-based Chronic Kidney Disease Epidemiological Collaboration (CKD-EPI) equation with body surface area indexation provided the most reliable clearance estimates. Simulations showed that CI regimens of 4-6 g/2-3 g daily achieved optimal target attainment (≥90%) across all kidney function strata for MICs up to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoint. Cumulative fraction of responses remained robust against key resistance phenotypes: MDR (12.6%; 83.8%), pan-beta-lactam-nonsusceptible (8.2%; 78.2%), and difficult-to-treat resistant (6.7%; 71.7%). Even among isolates with MIC >4 mg/L, aggressive target attainment was reached in 15%-40% of cases. This study suggests that CI ceftolozane/tazobactam, informed by TDM and optimized for aggressive PK/PD targets, offers a promising strategy to maximize efficacy and suppress resistance in severe <i>Pseudomonas aeruginosa</i> infections. These findings warrant prospective clinical trials of CI-based, exposure-guided therapy.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0104225"},"PeriodicalIF":4.5,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111842","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":"Metronidazole exposure-response and safety in infants.","authors":"Rachel L Randell, Stephen J Balevic, Rachel G Greenberg, Michael Cohen-Wolkowiez, Michael J Smith, Daniel K Benjamin, Catherine Bendel, Joseph M Bliss, Hala Chaaban, Rakesh Chhabra, Christiane E L Dammann, L Corbin Downey, Chi D Hornik, Naveed Hussain, Matthew M Laughon, Adrian Lavery, Fernando Moya, Matthew Saxonhouse, Gregory M Sokol, Andrea Trembath, Joern-Hendrik Weitkamp, Christoph P Hornik","doi":"10.1128/aac.00377-25","DOIUrl":"https://doi.org/10.1128/aac.00377-25","url":null,"abstract":"<p><p>The nitroimidazole antibiotic, metronidazole, is frequently prescribed to infants with serious intra-abdominal infections, and multiple dosing recommendations exist. We sought to evaluate the extent to which metronidazole doses and associated exposures achieved desired efficacy and safety in infants enrolled in the Antibiotic Safety in Infants with Complicated Intra-abdominal Infections (SCAMP) trial (NCT01994993). SCAMP participants received intravenous metronidazole as part of multimodal antimicrobial therapy. Participants received a 15 mg/kg loading dose and a 7.5 mg/kg maintenance dose at 24 h. A subsequent 7.5 mg/kg maintenance dose was administered every 12 h for participants of postmenstrual age (PMA) 23 to <34 weeks; 8 h for PMA 34-40 weeks; and 6 h for PMA >40 weeks. We evaluated associations between simulated metronidazole exposures and pre-specified surrogate pharmacodynamic targets and clinical outcomes of efficacy and safety. Nearly 100% of pharmacodynamic targets were met. Infants with therapeutic success (a composite efficacy outcome, defined as the absence of death, negative bacterial blood cultures, and presumptive clinical cure at 30 days) had higher <i>C</i>_min,ss, <i>C</i>_max,ss, AUC0_0-24,ss, and AUC_cum compared with infants without therapeutic success. However, the relationships between these exposure measures and therapeutic success were not significant in logistic regression analysis adjusting for gestational age. Despite generally high simulated exposures, no relationships were observed between exposures and prespecified safety events (necrotizing enterocolitis, intestinal strictures, intestinal perforation, positive blood culture, seizures, death, and intraventricular hemorrhage). Findings support metronidazole dosing as administered in term and preterm infants in the SCAMP trial.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0037725"},"PeriodicalIF":4.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084889","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":"Deconvoluting drug interactions using <i>M. tuberculosis</i> physiologic processes: transcriptional disaggregation of the BPaL regimen <i>in vivo</i>.","authors":"Elizabeth A Wynn, Christian Dide-Agossou, Reem Al Mubarak, Karen Rossmassler, Jo Hendrix, Martin I Voskuil, Andrés Obregón-Henao, Michael A Lyons, Gregory T Robertson, Camille M Moore, Nicholas D Walter","doi":"10.1128/aac.00492-25","DOIUrl":"https://doi.org/10.1128/aac.00492-25","url":null,"abstract":"<p><p>A key challenge in preclinical tuberculosis drug development is identifying optimal antibiotic combinations. Drug interactions are complex because one drug may affect <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) physiology in a way that alters the activity of another drug. Conventional pharmacodynamic evaluation based on colony-forming units (CFU) does not provide information about this physiologic interaction because CFU enumerates bacteria but does not give information about the drug's effect on bacterial cellular processes. SEARCH-TB is a novel pharmacodynamic (PD) approach that uses targeted <i>in vivo</i> transcriptional profiling to evaluate drug effects on <i>Mtb</i> physiology. To evaluate SEARCH-TB's capacity to elucidate drug interactions, we deconstructed the BPaL (bedaquiline, pretomanid, and linezolid) regimen in the BALB/c high-dose aerosol mouse infection model, measuring the effect of 2-, 7-, and 14-day treatment with drugs in monotherapy, pairwise combinations, and as a three-drug combination. Monotherapy induced drug-specific <i>Mtb</i> transcriptional responses by day 2 with continued evolution over 14 days. Bedaquiline dominated pairwise combinations with pretomanid and linezolid, whereas the pretomanid-linezolid combination induced a transcriptional profile intermediate between either drug. In the three-drug BPaL regimen, adding both pretomanid and linezolid to bedaquiline yielded a greater transcriptional response than expected, based on pairwise results. This work demonstrates that physiologic perturbations induced by a single drug may be modified in complex ways when drugs are combined. This establishes proof of concept that SEARCH-TB provides a highly granular readout of drug interactions <i>in vivo,</i> providing information distinct from CFU burden and suggesting a future where regimen selection is informed by <i>in vivo</i> molecular measures of <i>Mtb</i> physiology.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0049225"},"PeriodicalIF":4.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079472","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":"Correction for Siceloff et al., \"Antimicrobial Resistance Hidden within Multiserovar <i>Salmonella</i> Populations\".","authors":"Amy T Siceloff, Naomi Ohta, Keri N Norman, Guy H Loneragan, Bo Norby, H Morgan Scott, Nikki W Shariat","doi":"10.1128/aac.00926-25","DOIUrl":"https://doi.org/10.1128/aac.00926-25","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0092625"},"PeriodicalIF":4.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079545","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":"Colistin heteroresistance in <i>Enterobacter</i> due to base heterozygosity at certain <i>phoP</i> and <i>phoQ</i> locations.","authors":"Chengcheng Wang, Yu Feng, Zhiyong Zong","doi":"10.1128/aac.00713-25","DOIUrl":"https://doi.org/10.1128/aac.00713-25","url":null,"abstract":"<p><p>Colistin heteroresistance (CHR) is a growing concern in clinical settings. We aimed to investigate CHR for its prevalence in <i>Enterobacter</i> strains, its impact on colistin treatment, and its genetic mechanisms. We analyzed 109 non-duplicated <i>Enterobacter</i> strains isolated from blood cultures. Minimum inhibitory concentrations (MICs) of colistin for each strain were determined using microdilution and CHR was assessed by population analysis profile (PAP) assays. <i>In vitro</i> time-killing assays and <i>in vivo</i> murine intra-abdominal infection models were conducted to evaluate whether CHR contributes to colistin treatment failure. Whole genome sequencing and single nucleotide polymorphism (SNP) analysis were performed to uncover the genetic mechanisms associated with CHR, which were verified using cloning experiments. About 30% of colistin-susceptible <i>Enterobacter</i> strains exhibited CHR, which indeed increased treatment failures. Novel base alterations in the two-component system gene <i>phoP</i> or <i>phoQ</i> were identified as the mechanism for colistin resistance. The presence of such colistin-resistance-mediated base alterations in minor subpopulations of the same strain was detected, which generates base heterozygosity resulting in heterogeneity of colistin resistance. Colistin resistance can be mediated by various mutations in the same strain after exposure to colistin, which provides the flexibility to accommodate antimicrobial selection pressure. In conclusion, these findings allow us to disclose the genetic heterogeneity in CHR <i>Enterobacter</i> strains, which is consistent with \"phenotypic heterogeneity\" and provides genetic explanations for the dynamic heterogeneous resistance. Our study underscores the clinical significance of CHR and provides important insights and new perspectives into the mechanisms for the heterogeneity of antimicrobial resistance.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0071325"},"PeriodicalIF":4.5,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079547","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}