Antimicrobial Agents and Chemotherapy最新文献

{"title":"Clinical and genomic determinants associated with emergent ceftazidime-avibactam plus aztreonam non-susceptibility in ceftazidime-avibactam resistant <i>Escherichia coli</i>.","authors":"William C Shropshire, Jovan Borjan, Iris Y Fonseca, Kathlyn Pham, Melanie Guerrero, Karl Liboro, Allyson Young, Jovelle K Chung, Chin-Ting Wu, Ambrocio Manzanares, Micah M Bhatti, Nancy N Vuong, Guy Handley, Amy Spallone, Roy F Chemaly, Ayesha Khan, Samuel Shelburne","doi":"10.1128/aac.01860-25","DOIUrl":"10.1128/aac.01860-25","url":null,"abstract":"<p><p>Ceftazidime-avibactam (CZA) has revolutionized care for carbapenem-resistant Enterobacterales infections, yet increasing New Delhi metallo-β-lactamase (NDM) prevalence has driven use of CZA plus aztreonam (ATM/CZA). We performed a comprehensive clinical and genomic analysis of ceftazidime-avibactam-resistant <i>Escherichia coli</i> (CZA-R-<i>Ec</i>) collected at a tertiary cancer center (2017-2024) to identify patient- and isolate-level factors associated with reduced susceptibility to ATM/CZA and aztreonam-avibactam (AZA). CZA-R-<i>Ec</i> were isolated from 48 unique patients of whom 28 (58%) had confirmed infection. Oxford Nanopore Technologies long-read sequencing performed on 34 isolates from unique patients showed a diverse population enriched for ST167 (35%). Most sequenced isolates carried <i>bla</i>_NDM-5 (26/34, 76%); among <i>bla</i>_NDM-5 strains, 88% (23/26) harbored PBP3 YRI(K/N) insertions. Eleven isolates (32%) carried <i>bla</i>_CMY variants, predominantly <i>bla</i>_CMY-42. <i>Bla</i>_NDM-5 and <i>bla</i>_CMY genes were largely plasmid-borne (IncF-type and IncI-γ/K1) in distinct genomic contexts. Among 32 confirmed CZA-R and ATM-R index isolates, 21 (66%) were ATM/CZA susceptible (MIC≤4 µg/mL; ATM/CZA-S). Compared to patients with ATM/CZA-S strains, patients with ATM/CZA non-susceptible (ATM/CZA-NS) isolates (ATM/CZA MIC>4 µg/mL) were significantly more likely to have had a prior <i>E. coli</i> infection (73% vs 0%, <i>P</i>-value = 1.6 × 10^-5). ATM/CZA-NS isolates were strongly associated with <i>bla</i>_CMY carriage (81% vs 9% in ATM/CZA-S; adjusted <i>P</i>-value = 4 × 10^-4). Among 18 confirmed CZA-R-<i>Ec</i> bacteremias, 15 carried <i>bla</i>_NDM; 14/15 (92%) received ATM/CZA and all responded clinically. In conclusion, CZA-R-<i>Ec</i> at our center are dominated by PBP3-insertion, <i>bla</i>_NDM-5-positive lineages, for which ATM/CZA retains substantial <i>in vitro</i> activity and clinical efficacy. However, prior <i>E. coli</i> infection and <i>bla</i>_CMY-42 variant positivity identify patients at risk for ATM/CZA non-susceptible infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0186025"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147497545","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":"Peroxin Pex8 couples stress responses, antifungal tolerance, and virulence regulation in <i>Candida albicans</i>.","authors":"Bangsheng Xi, Yongqin Wu","doi":"10.1128/aac.01662-25","DOIUrl":"10.1128/aac.01662-25","url":null,"abstract":"<p><p><i>Candida albicans</i>, a World Health Organization critical-priority fungal pathogen, represents the predominant cause of candidemia. Therapeutic failure is sometimes driven by antifungal tolerance, a phenotype distinct from resistance, whose underlying mechanisms remain incompletely defined. Here, we identify the peroxisomal protein Pex8 as a key regulator of tolerance to both azoles and amphotericin B. Although neither deletion nor overexpression of <i>PEX8</i> altered minimum inhibitory concentrations, both modifications significantly reduced drug tolerance, as demonstrated by reduced fractional growth (FoG₂₀) and impaired survival under drug pressure. RNA-seq analysis showed that <i>PEX8</i> overexpression leads to downregulation of ergosterol biosynthesis genes and remodeling of stress-response pathways, suggesting a possible transcriptional basis for the loss of azole tolerance. Complementary lipidomic profiling demonstrated that <i>PEX8</i> genetic manipulations induce extensive membrane lipid remodeling, characterized by specific alterations in ceramide and lysophospholipid subclasses, thereby revealing an ergosterol-independent mechanism underlying amphotericin B tolerance attenuation. Phenotypically, <i>PEX8</i> overexpression attenuated serum-induced hyphal morphogenesis and reduced virulence in a <i>Galleria mellonella</i> infection model, consistent with downregulation of hyphal-associated and virulence-related genes. Our findings establish Pex8 as a central coordinator of oxidative stress adaptation, membrane homeostasis, filamentation, and pathogenicity, revealing a promising target for combating antifungal tolerance.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0166225"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148049/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502848","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":"Comparative <i>in vitro</i> efficacy of aztreonam-avibactam and other alternatives (cefepime-taniborbactam, cefepime-zidebactam, and cefiderocol) against metallo-β-lactamase-producing Enterobacterales isolated in 2024 in France.","authors":"Cécile Emeraud, Marion Dutkiewicz, Laurent Dortet","doi":"10.1128/aac.00176-26","DOIUrl":"10.1128/aac.00176-26","url":null,"abstract":"<p><p>We evaluated the <i>in vitro</i> activity of aztreonam-avibactam and other agents against 593 metallo-β-lactamase (MBL)-producing Enterobacterales collected in France in 2024. Aztreonam-avibactam showed the highest activity (98% susceptible), with resistance mainly observed in NDM-5-producing <i>Escherichia coli</i> belonging to ST167, ST405, and ST361. Cefepime-zidebactam also exhibited strong activity (96.6% of susceptibility). Cefepime-taniborbactam and cefiderocol showed reduced overall activity (76.4% and 74.9% susceptibility, respectively), with reduced efficacy mainly observed among NDM-producing isolates. Comparison with 1,465 isolates from 2023 showed no increase in aztreonam-avibactam resistance.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0017626"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147525651","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":"Analysis of interactions between posaconazole/voriconazole and venetoclax.","authors":"Chunqing Liu, Xiaoyan Xie, Mei Sun, Pengzhou Hang, Jinxiu Lyu, Yibing Shi, Xiang Gao, Wenjun Xu, Hua Zhu","doi":"10.1128/aac.01101-25","DOIUrl":"10.1128/aac.01101-25","url":null,"abstract":"<p><p>Venetoclax (VEN), a selective BCL-2 inhibitor predominantly metabolized by CYP3A4, is a cornerstone therapeutic for myeloid neoplasms (MNs). Patients with myeloid malignancies are at elevated risk of invasive fungal infections (IFIs), and triazole antifungal drugs, such as posaconazole (PCZ) and voriconazole (VCZ), are commonly used for prophylaxis or treatment. These agents are potent CYP3A4 inhibitors and will exhibit significant potential for pharmacokinetic drug-drug interactions with VEN. Although studies on their interaction are limited, such combinations are frequently used in clinical practice, making further research highly significant. This study aimed to investigate the changes in blood concentration and the safety of VEN when combined with triazole antifungal drugs (PCZ and VCZ). Patients with MN treated with VEN from April 2023 to April 2025 were enrolled and allocated to the VEN monotherapy group and the VEN plus triazole antifungal drug group. We collected baseline demographic characteristics and monitored adverse events. Steady-state plasma concentrations of VEN were quantified using the liquid chromatography-mass spectrometry methodology. Statistical analyses, including comparative assessments of plasma concentrations and adverse event rates, were performed using IBM SPSS Statistics 26. A total of 54 patients were enrolled in the study. Following VEN dose reduction to 100 mg, plasma concentrations in the VEN + PCZ/VCZ group remained significantly elevated compared to the VEN group (<i>P</i> < 0.001). However, the magnitude of this elevation did not differ significantly between the VEN + PCZ group and the VEN + VCZ group (<i>P</i> = 0.176). In addition, there was no linear correlation between VEN concentration and PCZ/VCZ concentration. Safety analysis revealed no statistically significant differences between the two groups in the incidence of grade ≥3 hematological adverse events (<i>P</i> = 0.214) or severe (grade ≥3) gastrointestinal adverse events (<i>P</i> = 0.671). VEN combined with PCZ or VCZ resulted in significantly higher VEN exposure without a corresponding increase in severe hematological or gastrointestinal toxicity. This strategy effectively mitigates IFI risk without compromising the safety profile of VEN therapy.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0110125"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147589558","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":"Ceftazidime-avibactam resistance evolution in <i>Pseudomonas aeruginosa</i> and implications for cross-resistance to other novel β-lactams.","authors":"Ava J Dorazio, Ellen G Kline, Kevin M Squires, Sunish Shah, Daria Van Tyne, Janet Y Wu, Jason M Pogue, Ryan K Shields","doi":"10.1128/aac.01910-25","DOIUrl":"10.1128/aac.01910-25","url":null,"abstract":"<p><p>Twelve pairs of baseline and post-exposure <i>Pseudomonas aeruginosa</i> isolates from patients treated with ceftazidime-avibactam were evaluated to define mechanisms of treatment-emergent resistance. Resistance was associated with amino acid substitutions in ampC and OXA β-lactamases, or mutations in regulatory genes conferring hyper-production of AmpC and MexAB-OprM efflux pumps. Cross-resistance was common between ceftazidime-avibactam and ceftolozane-tazobactam, less common for imipenem-relebactam and cefepime-zidebactam, and lowest for cefiderocol. These findings have important implications for sequential treatment of <i>P. aeruginosa</i> infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0191025"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147621750","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":"Multidimensional assessment of in-host fitness costs of echinocandin resistance in the opportunistic fungal pathogen <i>Candida glabrata</i> reveals the niche-specific requirement for <i>FKS1</i> and <i>FKS2</i> during infection and gut colonization.","authors":"Amir Arastehfar, Farnaz Daneshnia, Hrant Hovhannisyan, Nathaly Cabrera, Sebastian Jusuf, Mostafa Salehi, Michael K Mansour, Toni Gabaldón, Erika Shor, David S Perlin","doi":"10.1128/aac.01801-25","DOIUrl":"10.1128/aac.01801-25","url":null,"abstract":"<p><p>Host stresses are often considered a major barrier against the emergence of echinocandin resistance (ECR) in prominent infecting organisms like <i>Candida albicans</i> due to fitness defects. Yet, ECR strains of <i>C. glabrata</i> carrying diverse amino acid changes in Fks1 and Fks2 are increasingly reported as breakthrough infections. Nonetheless, the impact of equivalent mutations in different <i>FKS</i> alleles on fitness has not been systematically studied. Herein, we employed a diverse array of <i>ex vivo</i> and <i>in vivo</i> models to address these questions among clinically relevant ECR mutants. All ECR mutants retained fitness during interaction with THP1 macrophages and neutrophils. Whereas a strain with a Fks2^F659del or <i>fks2Δ</i> showed fitness defects during interaction with macrophages and neutrophils. Fks2^F659del showed a unique susceptibility to numerous stresses, especially the combination of alternative carbon sources, low pH, and H₂O₂. Consistent with failure in mounting adaptive oxidative stress response during exposure to H₂O₂, transcriptomic analysis of intracellular Fks2^F659del highlighted the dysregulation of oxidative stress response genes, whereas intracellular <i>fks2Δ</i> showed hallmarks of metabolic dysregulation. Intriguingly, the Fks2^F659del mutant was outcompeted by wild type and Fks2^F659V in <i>in vivo</i> gut colonization and systemic infection models. Importantly, whereas both <i>FKS1</i> and <i>FKS2</i> were required to establish gut colonization, only <i>FKS2</i> was required for systemic infection. Therefore, our study supports the notion that the prevalence of ECR mutants among <i>C. glabrata</i> strains is likely driven by its ability to retain fitness across diverse niches. Furthermore, we identified that the essentiality of <i>FKS1</i> and <i>FKS2</i> is similarly dictated by niche-specific requirements.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0180125"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147497528","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":"<i>In vitro</i> selection and characterization of resistance to pristinamycin in <i>Mycoplasma genitalium</i>.","authors":"Chloé Le Roy, Jennifer Guiraud, Otgonjargal Byambaa, Carla Balcon, Léo Gillet, Jorgen S Jensen, Cécile Bébéar, Sabine Pereyre","doi":"10.1128/aac.00094-26","DOIUrl":"10.1128/aac.00094-26","url":null,"abstract":"<p><p>Pristinamycin, a streptogramin combination, is recommended as a third-line treatment for <i>Mycoplasma genitalium</i> infections according to European guidelines. However, the molecular mechanisms underlying pristinamycin resistance have not yet been elucidated. We investigated the <i>in vitro</i> development of pristinamycin-resistant <i>M. genitalium</i> mutants under exposure to subinhibitory concentrations of pristinamycin or josamycin. Resistant mutants were characterized by determining the MICs of seven antibiotics, performing Sanger sequencing of 23S rRNA and the ribosomal protein L4 and L22 genes, and conducting whole-genome sequencing in comparison with the parental, susceptible G37 reference strain. Mutants selected in the presence of pristinamycin harbored either an A2062C or A2062G mutation in 23S rRNA, both associated with a marked increase in the MICs of pristinamycin and josamycin. By contrast, selection with josamycin produced a mutant carrying the A2059G mutation, which exhibited elevated MICs for erythromycin, azithromycin, josamycin, and clindamycin, but not for pristinamycin. None of the three resistant mutants showed any detectable growth defect in culture. To mimic pristinamycin treatment in a macrolide-resistant background, further selection was performed using subinhibitory concentrations of pristinamycin on the azithromycin-resistant A2059G mutant. This led to the emergence of an additional C2611T substitution in 23S rRNA, resulting in a pristinamycin MIC of 8 mg/L. No stable mutations were observed in the ribosomal protein L4 or L22 genes during the selection process. In conclusion, this study demonstrates that pristinamycin resistance in <i>M. genitalium</i> is mediated by mutations in the 23S rRNA gene. These laboratory-derived mutations may foreshadow resistance mechanisms emerging in clinical isolates.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0009426"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147580304","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":"Establishment of epidemiological cutoff values for clinically relevant <i>Sporothrix</i> species using CLSI-broth microdilution.","authors":"Amanda R Dos Santos, Alexandro Bonifaz, Amanda Bombassaro, Ana Caroline de Sá Machado, Anderson M Rodrigues, Andrew M Borman, Arunaloke Chakrabarti, Anuradha Chowdary, Bruno Rediguieri, Elizabeth M Johnson, Ferry Hagen, Flavio Queiroz-Telles, Gloria M Gonzalez, Guillermo Garcia-Effron, Isabella Dib Ferreira Gremião, Jacques F Meis, Juliana Possato Fernandes Takahashi, Luana Pereira Borba Dos Santos, Marcia S C Melhem, Paola Cappellano, Raimunda Sâmia Nogueira Brilhante, Sandro Antonio Pereira, Sarah Santos Gonçalvez, Sarah Kidd, Sean X Zhang, Shivaprakash Rudramurthy, Sonia Rozental, Susana Cordoba, Theun De Groot, Wei Liu, Nathan P Wiederhold, Eelco F J Meijer, Shawn R Lockhart, Philippe J Dufresne","doi":"10.1128/aac.01907-25","DOIUrl":"10.1128/aac.01907-25","url":null,"abstract":"<p><p>Sporotrichosis is a globally distributed subcutaneous mycosis caused mainly by <i>Sporothrix brasiliensis</i>, <i>S. schenckii</i>, and <i>S. globosa</i>. Cat-transmitted sporotrichosis, primarily caused by <i>S. brasiliensis</i> in South America and to a lesser extent by <i>S. schenckii</i> in Southeast Asia, is emerging as a substantial public health concern due to its outbreak potential. Itraconazole is the first-line drug for the treatment of humans and cats, but reduced susceptibility has been reported based on previously proposed epidemiological cut-off values (ECVs). To support resistance surveillance, we aimed to establish the Clinical and Laboratory Standards Institute (CLSI)-endorsed ECVs for these clinically relevant <i>Sporothrix</i> species. A total of 3,504 minimum inhibitory concentration (MIC) values for six antifungal agents (amphotericin B, itraconazole, posaconazole, voriconazole, isavuconazole, and terbinafine) were obtained from 19 international laboratories. Four of seven antifungals met the CLSI M57 guidelines criteria to determine the ECV. Established ECVs for amphotericin B were found to be high, with 8 µg/mL for <i>S. brasiliensis</i> and <i>S. globosa</i>, and 4 µg/mL for <i>S. schenckii</i>. Itraconazole ECVs were 4 µg/mL for <i>S. brasiliensis</i> and <i>S. schenckii</i>. Posaconazole ECVs were 4 µg/mL for all three species (tentative for <i>S. globosa</i>), while the terbinafine ECV for <i>S. brasiliensis</i> was 0.12 µg/mL. Overall, this study establishes validated ECVs for key antifungals against <i>Sporothrix</i> species and identifies a low prevalence of non-wild-type (NWT) isolates (<10% except for <i>S. schenckii</i> and posaconazole), supporting ongoing antifungal resistance monitoring.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0190725"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147621711","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":"Evaluating the efficacy of ceftazidime/avibactam plus amikacin combination therapy as a carbapenem-sparing agent against ceftazidime/avibactam-resistant <i>Escherichia coli</i> using a hollow fiber infection model: a proof-of-concept study.","authors":"Mikaela M Walker, Jason A Roberts, Yixuan Li, Saiyuri Naicker, Steven C Wallis, Jenny L Ordonez, Hayoung Won, Brian M Forde, Fekade B Sime","doi":"10.1128/aac.01377-25","DOIUrl":"https://doi.org/10.1128/aac.01377-25","url":null,"abstract":"<p><p>Carbapenems, often regarded as the last line of defense in treatment of urinary tract infections and urosepsis caused by <i>Escherichia coli</i>, are under pressure from emerging resistance. Thus, it is necessary to investigate carbapenem-sparing agents to mitigate the dissemination of carbapenem resistance. In this study, we aimed to evaluate the efficacy of ceftazidime/avibactam plus amikacin combination therapy against two ceftazidime/avibactam-resistant <i>E. coli</i> clinical isolates harboring IMP-4 carbapenemase (CTAP #226 and CTAP #233). To achieve this, we used a hollow fiber infection model (HFIM) with clinically relevant regimens of amikacin (15 mg/kg q24h) and ceftazidime/avibactam (2 g ceftazidime/0.5 g avibactam q8h), which were administered to the HFIM either alone or in combination over a 7-day treatment course. Initial inoculum was ~1 × 10⁷ CFU/mL. Both amikacin and ceftazidime/avibactam monotherapies resulted in bacterial killing (~4 log₁₀ and ~3 log₁₀, respectively) within the first 8 h; however, regrowth surpassing the baseline was observed over the following 7 days. Conversely, combination therapy resulted in bacterial killing to <the limit of quantification (10² CFU/mL) within the first 48 h, which was sustained for the entirety of the experiment. This study showed that the combination of amikacin and ceftazidime/avibactam was superior to both monotherapies and therefore presents a promising carbapenem-sparing option for the treatment of ceftazidime/avibactam-resistant <i>E. coli</i>. Further clinical studies are required to assess the suitability for use <i>in vivo</i>.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0137725"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831775","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 and genetics of cefepime resistance among the AmpC-producing organisms <i>Citrobacter freundii</i> complex, <i>Enterobacter cloacae</i> complex, and <i>Klebsiella aerogenes</i>.","authors":"Sarah M Schrader, Zachary Pearson, Samantha Taffner, Sanjat Kanjilal, Nicole D Pecora","doi":"10.1128/aac.01661-25","DOIUrl":"10.1128/aac.01661-25","url":null,"abstract":"<p><p>Cefepime is generally recommended for treatment of clinically significant AmpC producers, including <i>Citrobacter freundii</i> complex (<i>Cfre</i>), <i>Enterobacter cloacae</i> complex (<i>Eclo</i>), and <i>Klebsiella aerogenes</i> (<i>Kaer</i>). Clinicians increasingly use the results of multiplex PCR panels to make early treatment decisions, with cefepime often chosen when an AmpC producer is detected without a <i>bla</i>_CTX-M extended-spectrum beta-lactamase (ESBL) or carbapenemase. To understand the safety of this approach, we evaluated the prevalence of cefepime resistance among 4,687 <i>Cfre</i>; 9,878 <i>Eclo</i>; and 4,800 <i>Kaer</i> clinical isolates collected in our hospital network in New England, USA, from 2015 to 2024. We additionally reviewed Blood Culture Identification 2 (BCID2) (bioMérieux) results for 136 blood cultures and the sequenced genomes of 184 isolates (14 cefepime-susceptible dose-dependent [SDD], 34 cefepime-resistant). Cefepime-SDD and cefepime-resistant isolates made up 0.4% (18/4,687) and 1.3% (59/4,687) of <i>Cfre</i>, 2.0% (194/9,879) and 3.0% (299/9,879) of <i>Eclo</i>, and 0.3% (16/4,800) and 0.6% (28/4,800) of <i>Kaer</i>. Of 117 <i>Eclo</i> and <i>Kaer</i> identified in blood cultures on the BCID2, 4.3% (5/117) were cefepime-SDD or cefepime-resistant and negative for an ESBL or carbapenemase target. Among sequenced cefepime-SDD isolates, 21% (3/14) carried an ESBL. Cefepime-resistant isolates carried diverse beta-lactamase genes, including ESBL genes, carbapenemase genes, and plasmid-borne <i>ampC</i>. While reduced cefepime susceptibility was generally associated with carriage of more beta-lactamase genes, 57% of cefepime-SDD and 35% of cefepime-resistant isolates encoded only chromosomal <i>ampC</i>. Our results highlight variable cefepime susceptibility rates for AmpC producers across clinical settings and demonstrate diverse mechanisms underlying reduced cefepime susceptibility.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0166125"},"PeriodicalIF":4.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147525620","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}