Antimicrobial Agents and Chemotherapy最新文献

{"title":"A microbiological and structural analysis of the interplay between sulbactam/durlobactam and imipenem against penicillin-binding proteins (PBPs) of <i>Acinetobacter</i> spp.","authors":"Balaji Veeraraghavan, Eunjeong Shin, Yamuna Devi Bakthavatchalam, Abi Manesh, Dilip Dubey, Carlo Tascini, Magdalena A Taracila, Andrea M Hujer, Michael R Jacobs, Robert A Bonomo","doi":"10.1128/aac.01627-24","DOIUrl":"10.1128/aac.01627-24","url":null,"abstract":"<p><p>In the ATTACK Phase 3 trial examining the efficacy of sulbactam (SUL)/durlobactam (DUR) to treat primarily <i>Acinetobacter baumannii</i> complex (ABC) infections, imipenem (IPM)/cilastatin was added as a common therapy to both the SUL/DUR and the comparator colistin arms. This raised the question of whether the use of IPM in the SUL/DUR arm of the study influenced the efficacy of SUL/DUR. To investigate this issue on a microbiological and molecular level, we performed static concentration time-kill studies and molecular modeling of binding of SUL to PBP1a and PBP3, IPM to PBP1a, PBP2, and PBP3, and DUR to OXA-23 and OXA-51. The time-kill studies performed using carbapenemase- and non-carbapenemase-producing isolates demonstrated synergy between SUL and IPM in the presence of DUR, supporting the notion that the efficacy of the SUL/DUR arm against <i>Acinetobacter</i> spp. in the ATTACK trial was enhanced by the addition of IPM. We also hypothesize that the protection of SUL and IPM from OXA carbapenemases by DUR enabled IPM and SUL to synergistically deactivate multiple PBPs (\"target redundancy\"). Docking simulations supported the favorable binding of SUL to PBP1a and PBP3, resulting in the formation of acyl-enzyme complexes. Molecular docking analysis of OXA carbapenemase enzymes with DUR also revealed favorable interactions. Although clinical trials are warranted, these analyses provide mechanistic support for the addition of IPM to SUL/DUR.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0162724"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539945","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":"Multicenter, retrospective cohort study of antimycobacterial treatment-related harms among patients with non-tuberculosis <i>Mycobacterium</i> infections in the United States.","authors":"Michael P Veve, Rachel M Kenney, Alisar M Aljundi, Michelle S Dierker, Vasilios Athans, Anita B Shallal, Nimish Patel","doi":"10.1128/aac.01596-24","DOIUrl":"10.1128/aac.01596-24","url":null,"abstract":"<p><p>Non-tuberculosis mycobacteria (NTM) are extensively drug-resistant organisms that require long-term therapy. The study purpose was to quantify the incidence of and risk factors for antimycobacterial-associated adverse drug events (ADEs) in persons with NTM infections receiving outpatient therapy. A multicenter, retrospective cohort was performed of persons with NTM infections who received antimycobacterial treatment from 2013 to 2024. Inclusion criteria were age ≥18 years, ≥1 month of outpatient treatment, and ≥1 follow-up outpatient visit within 3 months of index encounter. <i>Mycobacterium avium</i> complex and <i>Mycobacterium tuberculosis</i> complex were excluded. The primary outcome was development of pre-specified treatment-related ADE or acute kidney injury (AKI), thrombocytopenia, and/or <i>Clostridioides difficile</i> infection (CDI) through 12 months of therapy. Secondary outcomes included therapy discontinuation due to any treatment-related ADEs. Two hundred patients were included: 14% developed a pre-specified ADE. <i>Mycobacterium abscessus</i> (29%) was the most common pathogen; most initial regimens included a macrolide (54%), systemic aminoglycoside (24%), β-lactam (24%), or tetracycline derivative (22%). The most common pre-specified ADEs were thrombocytopenia (9%), AKI (8%), and CDI (<1%). The median (IQR) time-to-ADE was 25 (18-38) days from initial outpatient regimen; patients who received aminoglycoside- or oxazolidinone-based therapies were more likely to develop a pre-specified ADE (adjOR, 3.9; 95% CI, 1.7-9.2). Therapy discontinuation due to any ADE occurred in 35% of patients; the median (IQR) time-to-any ADE was 32 (21-58) days. ADEs in persons with NTM infections are common and occur near the first month of outpatient treatment. Intensified monitoring and/or use of more tolerable antimycobacterial regimens early in treatment may be an appropriate approach to avoid harms.Treatment of non-tuberculosis mycobacteria is complicated by adverse drug events (ADEs). This work quantified the incidence and time course of pre-determined, clinically relevant ADEs (acute kidney injury, thrombocytopenia, and <i>C. difficile</i> infection), which occurred in 14% of patients within 30 days of outpatient treatment.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0159624"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540012","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":"The efficacy of a regimen comprising clarithromycin, clofazimine, and bedaquiline in a mouse model of chronic <i>Mycobacterium avium</i> lung infection.","authors":"Binayak Rimal, Ruth A Howe, Chandra Panthi, Gyanu Lamichhane","doi":"10.1128/aac.01853-24","DOIUrl":"10.1128/aac.01853-24","url":null,"abstract":"<p><p><i>Mycobacterium avium,</i> a leading nontuberculous mycobacterium (NTM) pathogen, causes chronic pulmonary infections, particularly in individuals with underlying lung conditions or immunosuppression. Current treatments involve prolonged multidrug regimens with poor outcomes and significant side effects, highlighting the urgent need for improved therapies. Using a BALB/c mouse model of chronic <i>M. avium</i> pulmonary disease, we evaluated the efficacy of individual antibiotics-clarithromycin, clofazimine, and rifabutin-and combination regimens including clarithromycin + bedaquiline and clarithromycin + clofazimine + bedaquiline. Clarithromycin demonstrated potent bactericidal activity, reducing lung bacterial burden by 2.2 log₁₀ CFU, while clofazimine transitioned from bacteriostatic to bactericidal, achieving a 1.7 log₁₀ CFU reduction. Rifabutin was bacteriostatic against <i>M. avium</i> MAC 101 but ineffective against MAC 104. The triple-drug regimen of clarithromycin + clofazimine + bedaquiline was the most effective, achieving a 3.3 log₁₀ CFU reduction in bacterial load, with 98% clearance within the first week and continued efficacy over 8 weeks. Gross pathology confirmed these results, with granulomatous lesions observed only in untreated or rifabutin-treated mice. Combination therapy demonstrated enhanced efficacy compared to monotherapy. The findings underscore the potential of oral clarithromycin + clofazimine + bedaquiline or clarithromycin + clofazimine regimen as a promising therapeutic strategy for <i>M. avium</i> pulmonary disease.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0185324"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623307","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":"Triple antimicrobial combinations with potent synergistic activity against <i>M. abscessus</i>.","authors":"Yanqin Huang, Lucius Chiaraviglio, Ibidunni Bode-Sojobi, James E Kirby","doi":"10.1128/aac.01828-24","DOIUrl":"10.1128/aac.01828-24","url":null,"abstract":"<p><p>Synergy of antimicrobial combinations was tested against contemporary <i>Mycobacteroides abscessus</i> isolates using 2D and 3D checkerboard assays. Triple combinations of omadacycline-azithromycin-clofazimine, tigecycline-azithromycin-clofazimine, omadacycline-azithromycin-linezolid, and omadacycline-azithromycin-contezolid demonstrated synergy (fractional inhibitory concentration index ≤ 0.5) against 33%, 31%, 62%, and 66% of isolates, respectively. Notably, in all triple combinations, macrolide-resistant <i>M. abscessus</i> subsp. <i>abscessus</i> and <i>M. abscessus</i> subsp. <i>bolletii</i> isolates were fully sensitized to azithromycin at the FIC index, as were isolates with elevated clofazimine MICs.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0182824"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623310","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":"Combination therapy delays antimicrobial resistance after adaptive laboratory evolution of <i>Staphylococcus aureus</i>.","authors":"Maiken Engelbrecht Petersen, Amanda Batoul Khamas, Lars Jørgen Østergaard, Nis Pedersen Jørgensen, Rikke Louise Meyer","doi":"10.1128/aac.01483-24","DOIUrl":"10.1128/aac.01483-24","url":null,"abstract":"<p><p>Antibiotic resistance, driven by misuse and overuse of antibiotics, is one of the greatest threats against human health. The antimicrobial pressure during prolonged antibiotic treatment of chronic bacterial infections selects for resistance. While antibiotic combinations may reduce resistance emergence, antibiotic-tolerant persister cells can serve as a reservoir for resistance development. Therefore, targeting these cells with anti-persister drugs might provide a novel strategy for resistance prevention. In this study, we conducted 42 days of adaptive laboratory evolution using <i>Staphylococcus aureus</i> exposed to rifampicin, ciprofloxacin, daptomycin, and vancomycin, alone or in combination with the anti-persister drug mitomycin C. We monitored antibiotic susceptibility daily and assessed phenotypic changes in growth and biofilm formation in evolved strains. Whole-genome sequencing revealed mutations linked to antibiotic resistance and phenotypic shifts. Rifampicin resistance developed within a few days, while ciprofloxacin and daptomycin emerged in approximately 3 weeks. Treatments with vancomycin or mitomycin C resulted in minimal changes in susceptibility. While combination therapy delayed resistance, it did not fully prevent it. Notably, the combination of rifampicin with mitomycin C maintained rifampicin susceptibility throughout the long-term evolution experiment. Sub-inhibitory antibiotic treatments selected for both previously characterized and novel mutations, including unprecedented alterations in the nucleotide excision repair system and azoreductase following mitomycin C exposure. The delayed resistance development observed with combination therapy, particularly mitomycin C's ability to suppress rifampicin resistance, suggests potential therapeutic applications. Future studies should evaluate the clinical efficacy of anti-persister drugs in preventing resistance across different bacterial pathogens and infection models.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0148324"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963546/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623302","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":"Efficacy and safety of early antibiotic de-escalation in febrile neutropenia for patients with hematologic malignancy: a systematic review and meta-analysis.","authors":"Yu-Han Chen, Andrea Yue-En Sun, Karishma Narain, Wei-Cheng Chang, Chieh Yang, Po-Huang Chen, Hong-Jie Jhou, Ming-Shen Dai, Natasha Rastogi, Cho-Hao Lee","doi":"10.1128/aac.01597-24","DOIUrl":"10.1128/aac.01597-24","url":null,"abstract":"<p><p>Febrile neutropenia (FN) is a serious complication in patients with hematologic malignancies following treatments such as chemotherapy and hematopoietic stem cell transplantation. It is typically managed with broad-spectrum antibiotics (BSA), but the optimal duration of BSA therapy remains controversial. This meta-analysis aimed to assess the clinical efficacy and safety of early antibiotic de-escalation in patients with hematologic malignancies with FN before hematopoietic recovery, compared to those who continued BSA until hematopoietic recovery. Statistical analysis included pooled odds ratios (OR) for mortality and secondary adverse outcomes, along with subgroup analysis to identify patient populations that may benefit from early de-escalation. Ten studies, mostly retrospective observational designs, were included. Early de-escalation significantly reduced mortality risk (OR 0.20, 95% CI 0.06-0.69). Subgroup analyses showed mortality benefits in older patients (>55 years old, OR 0.42, 95% CI 0.18-0.98) and in higher-quality studies (OR 0.07, 95% CI 0.01-0.62). No significant differences were observed for infection-related ICU admissions, bacteremia, recurrent fever, or <i>Clostridium difficile</i> infection (CDI). In conclusion, early de-escalation of BSA in patients with hematologic malignancies and developing FN after treatment significantly reduces mortality risk without increasing major adverse events. These findings support the use of early de-escalation and highlight the need for personalized strategies to improve patient outcomes.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0159724"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623303","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":"Optimizing phage therapy for carbapenem-resistant <i>Enterobacter cloacae</i> bacteremia: insights into dose and timing.","authors":"Shi-Yong Fu, Xiu-Zhen Chen, Peng-Cheng Yi, Jie Gao, Wei-Xiao Wang, Shuang-Lin Gu, Jing-Han Gao, Du-Xian Liu, Han-Feng Xu, Yi Zeng, Chun-Mei Hu, Qin Zheng, Wei Chen","doi":"10.1128/aac.01683-24","DOIUrl":"10.1128/aac.01683-24","url":null,"abstract":"<p><p>The increase in multidrug-resistant (MDR) <i>Enterobacter cloacae</i> complex (ECC) infections, particularly those resistant to carbapenems, underscores the urgent need for alternative therapies. Phage therapy, with its specific bactericidal action, offers a promising solution. However, there remains a shortage of well-characterized ECC-targeting phages, and dosing and timing optimization for ECC-specific phage cocktails is largely unexplored. In this study, we isolated and characterized three novel lytic phages with diverse genome sizes and host ranges. Notably, ФEBU8 demonstrated broad-spectrum activity, lysing both <i>Enterobacter</i> species and <i>Acinetobacter baumannii</i>. ФECL22 displayed stability across a wide temperature range (4-50°C), pH tolerance (6-10), and a burst size of 19 PFU/cell, with OmpA identified as its receptor. Our formulated phage cocktail, comprising ФEBU8, ФECL22, and ФECL30, effectively rescued mice with <i>E. cloacae</i> bacteremia in a dose-dependent manner, with a mid-dose regimen showing particularly strong efficacy. Immediate phage administration achieved full survival, whereas a combined prophylactic and therapeutic regimen (\"-24 + 6\") also resulted in 100% survival. These findings highlight the critical roles of dosing and timing in optimizing phage therapy for carbapenem-resistant <i>Enterobacter</i> infections, with prophylactic use providing a valuable window for delayed treatment and a promising strategy for combating severe bacterial infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0168324"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143498082","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A call for healing and unity.","authors":"Patrick D Schloss","doi":"10.1128/aac.00308-25","DOIUrl":"10.1128/aac.00308-25","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0030825"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514486","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":"Evaluation of omadacycline <i>in vitro</i> activity against <i>Corynebacterium</i> species.","authors":"Saltanat Ualiyeva, Justin McCallum, Alexander Donald Pyden, Zoe Freeman Weiss","doi":"10.1128/aac.01864-24","DOIUrl":"10.1128/aac.01864-24","url":null,"abstract":"<p><p><i>Corynebacterium</i> spp. are gram-positive bacteria increasingly recognized as pathogens. This study evaluates the MICs of omadacycline, a tetracycline, against 40 clinical <i>Corynebacterium</i> isolates using two methodologies: broth microdilution (BMD) and Liofilchem omadacycline MIC Test Strip (MTS). By BMD, the MIC₅₀, MIC₉₀, and MIC range were 0.5 µg/mL, 1 µg/mL, and 0.12-2.0 µg/mL, respectively. Comparing BMD to MTS, essential agreement (EA, within ±1 doubling dilution of the reference BMD MIC) was 87.5% (95% CI: 73.0%-95.4%).</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0186424"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A call for the United States to continue investing in science.","authors":"Ira Blader, Felicia Goodrum, Michael J Imperiale, Arturo Casadevall, Cesar A Arias, Andreas Baumler, Carey-Ann D Burnham, Christina A Cuomo, Corrella S Detweiler, Graeme N Forrest, Jack A Gilbert, Susan Lovett, Stanley Maloy, Alexander McAdam, Irene Newton, Gemma Reguera, George A O'Toole, Patrick D Schloss, Ashley Shade, Marvin Whiteley","doi":"10.1128/aac.00319-25","DOIUrl":"10.1128/aac.00319-25","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":" ","pages":"e0031925"},"PeriodicalIF":4.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514487","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}