Antimicrobial Agents and Chemotherapy最新文献

{"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":"https://doi.org/10.1128/aac.00594-25","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0059425"},"PeriodicalIF":4.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of an electronic antibiotic time-out best practice alert on antibiotic use and prescribing behavior in hospitalized patients.","authors":"Tyler Ackley, Joseph Kuti, Anastasia Bilinskaya, Kristin Linder, Casey Dempsey","doi":"10.1128/aac.01680-24","DOIUrl":"https://doi.org/10.1128/aac.01680-24","url":null,"abstract":"<p><p>Provider-directed electronic antibiotic time-outs (ATOs) are a stewardship strategy capable of efficient and widespread impact with relatively low perceived personnel effort. This is a multi-center, quasi-experimental, retrospective chart review of patients admitted receiving empiric antibiotics for >72 hours. An ATO alert was designed and embedded within the electronic medical record and set to fire between the hours of 07:00 and 16:30 daily. Seventy-two hours after a unique antibiotic order was entered, a best practice alert (BPA) would fire for the primary team-including the attending physician, residents, and advanced practice providers-as well as any infectious disease provider consulted at the time of ATO firing. This alert is triggered when entering or modifying orders as an active pop-up to the ordering prescriber. Prescribers were then prompted to assess the patient for potential antibiotic optimization-including discontinuation, de-escalation, and transition to oral therapies. A total of 800 patients receiving >72 hours of antibiotics were included for analysis. There was no statistically significant difference in the rate of antibiotic optimization when comparing the pre- and post-implementation cohort (54.5% vs 57.5%, <i>P</i> = 0.433); however, there was a numerically lower rate of antibiotic escalation in the post-cohort (9.5% vs 5.8%, <i>P</i> = 0.062). Duration of antibiotic therapy was longer in the post-implementation cohort (4.7 vs 5.0 days, <i>P</i> < 0.001). The implementation of an ATO BPA failed to improve the rates of antibiotic optimization.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0168024"},"PeriodicalIF":4.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109306","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 pharmacokinetics of penicillin G: insights into increased clearance at low concentrations to guide development of improved long-acting formulations for syphilis and prevention of rheumatic fever.","authors":"Okhee Yoo, Sam Salman, Thel K Hla, Joshua Osowicki, Madhu Page-Sharp, Julie A Marsh, Renae Barr, Kristy Azzopardi, Michael Morici, Kevin T Batty, Stephanie L Enkel, Joseph Kado, Lara Hatchuel, Alma Fulurija, James S McCarthy, Thomas Snelling, Andrew C Steer, Jonathan Carapetis, Laurens Manning","doi":"10.1128/aac.00269-25","DOIUrl":"https://doi.org/10.1128/aac.00269-25","url":null,"abstract":"<p><p>Although benzylpenicillin (penicillin G) is listed by the World Health Organization as an Essential Medicine, dose optimization is a persistent challenge, especially for long-acting intramuscular formulations. Maintaining sustained antibiotic exposure at target concentrations is crucial for secondary chemoprophylaxis of rheumatic heart disease and treatment of syphilis. This study compared the pharmacokinetic profile of continuous low-dose benzylpenicillin infusions with a standard-dose bolus and evaluated which renal function marker (serum creatinine, cystatin C, or combined e-glomerular filtration rate [eGFR]) best predicted clearance. Healthy adult volunteers received a single 600 mg IV benzylpenicillin bolus followed by randomization to continuous infusions targeting steady-state concentrations of 3, 6, 9, 12, or 20 ng/mL. Plasma benzylpenicillin concentrations were measured by liquid chromatography-mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM by incorporating both bolus and infusion data, and various GFR estimations were evaluated as covariates for clearance. Data from 72 participants were analyzed, including 504 bolus and 389 continuous infusion samples. A two-compartment model improved fit when the ratio of central volume of distribution between bolus and low-dose infusion was incorporated, and clearance differences at steady state plasma concentration of 3 ng/mL were accounted for. Of the GFR estimations, cystatin C-based eGFR significantly enhanced model fit compared with creatinine-based equations. Benzylpenicillin pharmacokinetics at very low concentrations demonstrated both a higher volume of distribution and increased clearance. Cystatin C-based eGFR may more accurately predict benzylpenicillin clearance, enabling precision dosing for long-acting preparations used for treatment of syphilis and prevention of rheumatic fever.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0026925"},"PeriodicalIF":4.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109299","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":"Classic and new candidate markers for drug resistance in a large cohort of leprosy patients from the Amazon state, Brazil.","authors":"Cynthia de Oliveira Ferrreira, André Luiz Leturiondo, Camila Gurgel Dos Santos, Jaqueline Bentes da Silva, Michelle Fernanda de Andrade Souza, Catherine Bianca Oliveira Rego, Guilherme Caldas de Souza, Thamires Bastos Pinheiro, Gisely Cardoso Melo, Patricia Sammarco Rosa, Marcelo Távora Mira, Charlotte Avanzi, Carolina Talhari","doi":"10.1128/aac.01550-24","DOIUrl":"https://doi.org/10.1128/aac.01550-24","url":null,"abstract":"<p><p>Multidrug therapy for leprosy is highly effective and the recommended standard of care for leprosy worldwide. However, reports of antimicrobial resistance (AMR) have emerged globally. This study aimed to estimate the frequency of primary and secondary AMR associated with leprosy in patients treated at the Alfredo da Matta Foundation, Manaus, Amazonas, Brazil, as well as to determine the circulating subtypes of <i>Mycobacterium leprae</i> in this population. A total of 315 biopsy samples were investigated for variants in leprosy AMR-associated genes (<i>rpoB, folP1, gyrA</i>); a subset of 163 samples was also investigated for 5 additional candidate genes: <i>gyrB, ctpC, ctpI, ribD</i>, and <i>fadD9</i>. Patients were categorized into new cases, relapses, and suspected treatment failures. For statistical analysis, Pearson's chi-square or Fisher's exact test was employed for categorical variables, while mean and SD were calculated for continuous variables, with a significance level of 5%. Variant analysis detected 10 resistant <i>M. leprae</i> isolates displaying mutations in the <i>rpoB</i> (2, 0.6%) and <i>folP1</i> (8, 2.5%) genes. In addition, variants in <i>gyrB</i> (1, 0.6%), <i>ctpC</i> (6, 3.7%), <i>ribD</i> (4, 2.4%), and <i>fadD9</i> (15, 9.2%) were detected. Nine out of 10 resistant isolates were observed in the relapse group (<i>P</i> = 0,0014). Despite the low variant frequencies observed, variant detection highlights the need for expanded antimicrobial monitoring and surveillance. The impact of mutations in <i>ribD</i> and <i>fadD9</i> on therapeutic response remains unclear, underscoring the need for further research. Genotyping revealed subtype-4 predominance (79.6%). Our findings highlight the importance of comprehensive AMR monitoring, particularly in relapse cases.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0155024"},"PeriodicalIF":4.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109555","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":"Optimizing cefazolin dosing for central nervous system infections: insights from population pharmacokinetics and Monte Carlo simulations.","authors":"C Tyler Pitcock, David S Burgess, Katie B Olney","doi":"10.1128/aac.01857-24","DOIUrl":"https://doi.org/10.1128/aac.01857-24","url":null,"abstract":"<p><p>Recent studies suggest that cefazolin represents an appropriate treatment option for methicillin-susceptible <i>Staphylococcus aureus</i> (MSSA) central nervous system (CNS) infections. Monte Carlo simulations were used to evaluate specific cefazolin dosing regimens to identify the optimal dosing strategy to ensure adequate probability of target attainment for treatment of MSSA CNS infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0185724"},"PeriodicalIF":4.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109286","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":"The novel polymyxin analogue SPR206 exhibits higher activity than colistin against both colistin-susceptible and colistin-resistant strains of <i>Acinetobacter baumannii</i>.","authors":"Michelle Outeda-García, Andrea Garcia-Pose, Paula Guijarro-Sánchez, Arianna Rodríguez-Coello, Gabriela Alejandra Báez-Barroso, Romina Maceiras, Isaac Alonso-García, Jorge Arca-Suárez, Juan C Vázquez-Ucha, German Bou, Alejandro Beceiro","doi":"10.1128/aac.01940-24","DOIUrl":"https://doi.org/10.1128/aac.01940-24","url":null,"abstract":"<p><p>Colistin resistance is increasing globally and complicates treatments of <i>A. baumannii</i> infections. The next-generation polymyxin SPR206 shows potent activity against multidrug-resistant Gram-negative pathogens with low toxicity. SPR206 exhibited higher activity against colistin-susceptible and colistin-resistant strains (MIC₅₀/MIC₉₀ = 0.12/0.25 mg/L), and resistance was only detected in 1/118 strains (MIC ≥4 mg/L). Mutations in <i>pmrCAB</i>, linked to colistin resistance, do not seem to confer resistance to the novel polymyxin, which retains a high level of activity.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0194024"},"PeriodicalIF":4.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109304","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":"Evaluating tigecycline dosing for hospital-acquired pneumonia patients: insights from physiologically-based pharmacokinetic modeling of lung exposure.","authors":"Xiaonan Zhang, Feiyan Liu, Sanwang Li, Zeneng Cheng, Hanxi Yi, Feifan Xie","doi":"10.1128/aac.00004-25","DOIUrl":"https://doi.org/10.1128/aac.00004-25","url":null,"abstract":"<p><p>Tigecycline is increasingly used off-label for hospital-acquired pneumonia (HAP), though its efficacy and optimal dosing remain uncertain. Lung exposure to tigecycline may be affected by pulmonary pH changes induced by bacterial infections. This study used a physiologically -based pharmacokinetic (PBPK) model to evaluate the impact of pH shifts on lung exposure and assess the efficacy of various dosing regimens. A lung PBPK model for tigecycline was developed and validated using plasma and lung concentration data from clinical pharmacokinetic studies. Simulations evaluated the impact of pH alterations from 6.6 (healthy) to 5.6 (infection) on lung exposure. Three clinical dosing regimens-standard (100 mg loading dose +50 mg q12h), median (150 mg loading dose +75 mg q12h), and high dose (200 mg loading dose +100 mg q12h)-were assessed by calculating the probability of target attainment (PTA) in lung compartments, including epithelial lining fluid (ELF) and alveolar cells (ACs), across a MIC range of 0.125-32 mg/L. The model reasonably captured tigecycline exposure in plasma and lung. Pulmonary pH alterations had minimal impact on tigecycline AUC in ELF but led to a significant 12.39-fold increase in AUC within ACs at pH 5.6. For pathogens with MIC ≤1 mg/L, all three dosing regimens achieved PTA ≥90% in ELF. However, for MIC >2 mg/L, only the high-dose regimen provided satisfactory PTA. The lung PBPK model provides valuable insights into tigecycline PK in HAP patients and underscores the need to optimize dosing for pneumonia with resistant pathogens.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0000425"},"PeriodicalIF":4.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109295","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":"Characterization of genome-wide transpositions induced by colistin exposure in multi-drug-resistant <i>Klebsiella pneumoniae</i>.","authors":"Sahaya Glingston Rajakani, Basil Britto Xavier, Ngoc Minh Nguyen, Qiang Lin, Anouk Braspenning, Nienke L Plantinga, Bastiaan H J Wittekamp, Olympia Zarkotou, Rob Van Houdt, Youri Glupczynski, Spyros Pournaras, Marc J M Bonten, Surbhi Malhotra-Kumar","doi":"10.1128/aac.01574-24","DOIUrl":"https://doi.org/10.1128/aac.01574-24","url":null,"abstract":"<p><p>Colistin is one of the last-line antibiotics against multi-drug-resistant (MDR) gram-negative pathogens, such as <i>Klebsiella pneumoniae</i>. Using long-read sequencing, we observed remarkable genome-wide transposition events in MDR <i>K. pneumoniae</i> exposed to colistin in patients receiving treatment for respiratory infections or as part of selective decolonization strategies and further confirmed these on <i>in vitro</i> selection experiments. These data add yet another dimension to the role of antibiotics in mediating specific processes in bacteria beyond antibiotic resistance.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT02208154.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0157424"},"PeriodicalIF":4.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092624","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":"<i>In vitro</i> activity of novel antifungals, natamycin, and terbinafine against <i>Fusarium</i>.","authors":"Enrico Garbe, Ahsan Ullah, Alexander Maximilian Aldejohann, Oliver Kurzai, Slavica Janevska, Grit Walther","doi":"10.1128/aac.01913-24","DOIUrl":"https://doi.org/10.1128/aac.01913-24","url":null,"abstract":"<p><p>The genus <i>Fusarium</i> includes several trans-kingdom pathogens, infecting plants, animals, and humans, with widespread occurrence. Invasive <i>Fusarium</i> infections are often destructive due to their prevalence in critically ill patients. Furthermore, severe superficial infections, like keratitis or endophthalmitis with potential loss of vision, are rising in incidence globally. Infections are difficult to treat due to the intrinsic resistance of <i>Fusarium</i> against echinocandins and often high minimal inhibitory concentrations (MICs) for azoles. In this article, we assessed the <i>in vitro</i> activity of the novel antifungals olorofim, manogepix, rezafungin, and ibrexafungerp, as well as the established but nonstandard drugs, natamycin and terbinafine, against a large set of molecularly identified clinical <i>Fusarium</i> isolates via EUCAST microdilution. The tested isolates represent the clinically most relevant species of the <i>F. solani</i> (FSSC), <i>F. oxysporum</i> (FOSC), <i>F. fujikuroi</i> (FFSC), <i>F. incarnatum-equiseti</i> (FIESC), <i>F. dimerum</i> (FDSC), and <i>F. redolens</i> (FRSC) species complexes. While rezafungin and ibrexafungerp showed no effect on the <i>Fusarium</i> spp. tested, a general antifungal susceptibility of <i>Fusarium</i> against natamycin and manogepix was found. Specific profiles were detailed for terbinafine and olorofim. While species from the FDSC, FSSC, and FIESC show high MICs for olorofim, specific susceptibility rates were found for species of the FFSC and FOSC. Furthermore, we report specific susceptibilities for terbinafine against FDSC, FFSC, and FOSC species. These findings of complex- and species-specific olorofim and terbinafine <i>in vitro</i> susceptibilities highlight the need for diagnostics below genus level.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0191324"},"PeriodicalIF":4.1,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075544","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":"<i>In vitro</i> activity of gepotidacin against urinary tract infection isolates of Enterobacterales, <i>Enterococcus faecalis</i>, and <i>Staphylococcus saprophyticus</i>.","authors":"Meredith A Hackel, James A Karlowsky, Daniel F Sahm, Joshua M West, Nicole E Scangarella-Oman","doi":"10.1128/aac.00296-25","DOIUrl":"https://doi.org/10.1128/aac.00296-25","url":null,"abstract":"<p><p>Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication through a distinct binding site and unique mechanism of action, providing well-balanced inhibition of two different type II topoisomerase enzymes for most uropathogens. Phase III clinical trials, NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3), showed gepotidacin to be non-inferior and superior, respectively, to nitrofurantoin for the treatment of patients with uncomplicated urinary tract infections (uUTIs). To better define gepotidacin <i>in vitro</i> activity against pathogens that commonly cause UTIs, CLSI broth microdilution MICs were determined for gepotidacin and seven comparator agents, and agar dilution MICs were determined for fosfomycin, against 4,000 predominantly UTI isolates of Enterobacterales (3,250), <i>Enterococcus faecalis</i> (500), and <i>Staphylococcus saprophyticus</i> (250) collected globally from 2012 to 2020. Gepotidacin MIC₉₀s against the Enterobacterales species tested were 4 µg/mL for <i>Escherichia coli</i> (1,000) and <i>Klebsiella oxytoca</i> (250), 8 µg/mL for <i>Citrobacter</i> spp. (250) and <i>Klebsiella aerogenes</i> (250), 16 µg/mL for <i>Proteus mirabilis</i> (250) and <i>Providencia rettgeri</i> (250), and 32 µg/mL for <i>Enterobacter cloacae</i> (500) and <i>Klebsiella pneumoniae</i> (500). Against the gram-positive species, gepotidacin MIC₉₀s were 0.12 µg/mL and 4 µg/mL for <i>S. saprophyticus</i> (250) and <i>E. faecalis</i> (500), respectively. Gepotidacin MIC₉₀s for ciprofloxacin not susceptible isolates ranged from 4 µg/mL for <i>E. coli</i> (352) to 128 µg/mL for <i>P. rettgeri</i> (48). Gepotidacin MIC₉₀s for presumptive extended spectrum beta-laactamase (ESBL)-positive <i>E. coli</i> (228) and <i>K. pneumoniae</i> (145) were 8 µg/mL and 32 µg/mL, respectively. Gepotidacin was bactericidal (minimum bactericidal concentration [MBC]/MIC ratio ≤4) against 94% (47/50) of isolates tested.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0029625"},"PeriodicalIF":4.1,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075542","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}