Francesco Branda,Giancarlo Ceccarelli,Marta Giovanetti,Fabio Scarpa,Massimo Ciccozzi
{"title":"Polio-Free, Not Risk-Free: Wastewater as Early Warning.","authors":"Francesco Branda,Giancarlo Ceccarelli,Marta Giovanetti,Fabio Scarpa,Massimo Ciccozzi","doi":"10.1093/infdis/jiaf643","DOIUrl":"https://doi.org/10.1093/infdis/jiaf643","url":null,"abstract":"","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mia Aguirre,Doris Ayala,Juan Ignacio Garcia,Yoscelina E Martinez-Lopez,Amberlee D Hicks,Nadine Chacon,Ashley Gay-Cobb,Alyssa Schami,Selena Zavala-Perez,Ilse A Dominguez-Trejo,America M Cruz-Gonzalez,Raul Loera-Salazar,Javier E Rodríguez-Herrera,Esperanza M Garcia-Oropesa,Miryoung Lee,Adrian Rendón,Shu-Hua Wang,Marcel Yotebieng,Carlton A Evans,Jordi B Torrelles,Blanca I Restrepo
BACKGROUNDWith >10 million new tuberculosis (TB) cases/year, a limitation to TB control is the lack of simple and accurate tests for TB diagnosis and drug-susceptibility testing (DST) in endemic regions. We evaluated the accuracy of the first-generation, low-complexity phenotypic TB test (1G test), designed for simultaneous Mtb detection and resistance to isoniazid, rifampicin and moxifloxacin, suitable for resource-limited settings.METHODSA cross-sectional study was conducted using sputa from 426 possible pulmonary TB subjects from two small Mexican cities bordering Texas. The 1G test was compared against phenotypic TB detection tests in the region [acid fast bacilli smear microscopy and Mycobacteria Growth Indicator Tube (MGIT) culture], and to MGIT-DST for resistance to isoniazid, rifampicin and moxifloxacin.FINDINGSThe 1G test demonstrated ≥98% sensitivity for Mtb detection, 100% sensitivity and 91% (rifampicin), 94% (isoniazid) and 97% (moxifloxacin) specificity for DST, and less contamination than the MGIT (3.5% vs. 8.1%; p<0.05). The 1G test time to detection (TTD) of Mtb and simultaneous DST was 17-days, while the MGIT-DST required two steps: 7 days for Mtb detection plus 14 more (total 21 days) for DST. Our study site DR-TB prevalence was 14% when testing all consecutively-enrolled participants vs. 6% by passive reporting.INTERPRETATIONThe 1G test is a low-complexity phenotypic TB diagnostic method that is a practical replacement to current culture-based tests. Future studies are warranted to evaluate the implementation of the 1G test in decentralized clinics that lack molecular tools, resources and expertise.
背景：结核病流行地区每年新发结核病病例高达1000万，结核病控制面临的一个限制是缺乏简单而准确的结核病诊断和药敏试验（DST）检测。我们评估了第一代低复杂性表型结核试验（1G试验）的准确性，该试验设计用于同时检测结核分枝杆菌和对异烟肼、利福平和莫西沙星的耐药性，适用于资源有限的环境。方法横断面研究使用来自德克萨斯州边境两个墨西哥小城市的426名疑似肺结核患者的痰液。将1G试验与该地区[抗酸杆菌涂片镜检和分枝杆菌生长指示管（MGIT）培养]表型结核检测试验进行比较，并与MGIT- dst试验比较异烟肼、利福平和莫西沙星的耐药性。结果：1G试验对Mtb的检测灵敏度≥98%，对DST的检测灵敏度为100%，利福平为91%，异烟肼为94%，莫西沙星为97%，污染小于MGIT （3.5% vs. 8.1%; p<0.05）。Mtb和同步DST的1G检测到检测时间（TTD）为17天，而mgt -DST需要两个步骤：Mtb检测7天加上DST 14天（共21天）。在我们的研究现场，当对所有连续入组的参与者进行检测时，耐药结核病患病率为14%，而被动报告为6%。解释：1G测试是一种低复杂性的表型结核诊断方法，是目前基于培养的测试的实用替代品。未来的研究需要评估1G测试在缺乏分子工具、资源和专业知识的分散诊所中的实施情况。
{"title":"Accuracy of the phenotypic 1G test to detect Mycobacterium tuberculosis and drug resistance from sputa in the US-Mexico border.","authors":"Mia Aguirre,Doris Ayala,Juan Ignacio Garcia,Yoscelina E Martinez-Lopez,Amberlee D Hicks,Nadine Chacon,Ashley Gay-Cobb,Alyssa Schami,Selena Zavala-Perez,Ilse A Dominguez-Trejo,America M Cruz-Gonzalez,Raul Loera-Salazar,Javier E Rodríguez-Herrera,Esperanza M Garcia-Oropesa,Miryoung Lee,Adrian Rendón,Shu-Hua Wang,Marcel Yotebieng,Carlton A Evans,Jordi B Torrelles,Blanca I Restrepo","doi":"10.1093/infdis/jiaf638","DOIUrl":"https://doi.org/10.1093/infdis/jiaf638","url":null,"abstract":"BACKGROUNDWith >10 million new tuberculosis (TB) cases/year, a limitation to TB control is the lack of simple and accurate tests for TB diagnosis and drug-susceptibility testing (DST) in endemic regions. We evaluated the accuracy of the first-generation, low-complexity phenotypic TB test (1G test), designed for simultaneous Mtb detection and resistance to isoniazid, rifampicin and moxifloxacin, suitable for resource-limited settings.METHODSA cross-sectional study was conducted using sputa from 426 possible pulmonary TB subjects from two small Mexican cities bordering Texas. The 1G test was compared against phenotypic TB detection tests in the region [acid fast bacilli smear microscopy and Mycobacteria Growth Indicator Tube (MGIT) culture], and to MGIT-DST for resistance to isoniazid, rifampicin and moxifloxacin.FINDINGSThe 1G test demonstrated ≥98% sensitivity for Mtb detection, 100% sensitivity and 91% (rifampicin), 94% (isoniazid) and 97% (moxifloxacin) specificity for DST, and less contamination than the MGIT (3.5% vs. 8.1%; p<0.05). The 1G test time to detection (TTD) of Mtb and simultaneous DST was 17-days, while the MGIT-DST required two steps: 7 days for Mtb detection plus 14 more (total 21 days) for DST. Our study site DR-TB prevalence was 14% when testing all consecutively-enrolled participants vs. 6% by passive reporting.INTERPRETATIONThe 1G test is a low-complexity phenotypic TB diagnostic method that is a practical replacement to current culture-based tests. Future studies are warranted to evaluate the implementation of the 1G test in decentralized clinics that lack molecular tools, resources and expertise.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"118 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benedikt Strunz, Qiuyao Zhan, Tanvi Khera, Julia Hengst, Marija Jankovic, Katja Deterding, Annika Niehrs, Markus Cornberg, Cheng-Jian Xu, Heiner Wedemeyer, Niklas K Björkström
Acute infection with hepatitis C virus (HCV) is a rare event that can be treated successfully with direct-acting antivirals (DAAs). As Natural killer (NK) cells play an important role during the natural course of acute HCV, we assessed the NK cell compartment via flow cytometry and single-cell sequencing in longitudinally sampled patients with acute HCV and compared this to healthy controls and patients with chronic HCV. At the transcriptomic level, we identified a subset of highly activated NK cells with a robust type-I interferon imprint. While the population of activated NK cells vanished after DAA-mediated cure, a long-term phenotypic imprint of infection was observed in comparison to healthy controls. Collectively, these data suggest an interferon-driven rise of an activated NK cell population during acute hepatitis C, that is largely restored upon viral clearance. This study provides insights into the immunological basis for successful antiviral response to hepatitis C.
{"title":"Transient interferon-driven NK cell activation in acute hepatitis C","authors":"Benedikt Strunz, Qiuyao Zhan, Tanvi Khera, Julia Hengst, Marija Jankovic, Katja Deterding, Annika Niehrs, Markus Cornberg, Cheng-Jian Xu, Heiner Wedemeyer, Niklas K Björkström","doi":"10.1093/infdis/jiaf654","DOIUrl":"https://doi.org/10.1093/infdis/jiaf654","url":null,"abstract":"Acute infection with hepatitis C virus (HCV) is a rare event that can be treated successfully with direct-acting antivirals (DAAs). As Natural killer (NK) cells play an important role during the natural course of acute HCV, we assessed the NK cell compartment via flow cytometry and single-cell sequencing in longitudinally sampled patients with acute HCV and compared this to healthy controls and patients with chronic HCV. At the transcriptomic level, we identified a subset of highly activated NK cells with a robust type-I interferon imprint. While the population of activated NK cells vanished after DAA-mediated cure, a long-term phenotypic imprint of infection was observed in comparison to healthy controls. Collectively, these data suggest an interferon-driven rise of an activated NK cell population during acute hepatitis C, that is largely restored upon viral clearance. This study provides insights into the immunological basis for successful antiviral response to hepatitis C.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eyal Elias, Danielle Keidar-Friedman, Nadav Sorek, Orit Raz, Sharon Ovnat Tamir, Liam Aspit, Dan Bar Yaacov
Background Adenosine-to-inosine (A-to-I) mRNA editing can alter protein sequence and function, enabling bacteria to express two RNA and protein versions encoded by the same gene. However, its prevalence and significance in clinical bacterial settings remain unclear. Methods We collected ten Escherichia coli and seven Pseudomonas aeruginosa isolates from hospitalized patients with urinary tract infections (UTI) or ear infections. Whole-genome and transcriptome sequencing were performed for each isolate, followed by Sanger sequencing for selected sites. Results We present the first comprehensive analysis of A-to-I RNA editing in pathogenic bacteria isolated from hospitalized patients. We identified dozens of A-to-I RNA editing sites, including novel sites not previously reported in non-pathogenic E. coli and P. aeruginosa strains. We found that E. coli exhibits higher editing levels and a greater number of editing sites than P. aeruginosa. Most editing sites are embedded within a conserved 7-base motif and are frequently located in predicted stem-loop RNA secondary structures, highlighting the importance of both sequence and structure for editing site recognition in both the examined species. Most editing events occur in mRNA and often result in non-synonymous amino acid changes, with a notable prevalence of tyrosine-to-cysteine substitutions. Finally, we observed that editing patterns are similar between antibiotic-resistant and sensitive isolates, suggesting a more general role in the biology of the examined species. Conclusions A-to-I RNA editing is a feature of pathogenic bacteria isolated from clinical samples. Our findings expand current knowledge of bacterial RNA editing in clinical contexts and provide a framework for future functional investigations.
腺苷-肌苷（A-to-I） mRNA编辑可以改变蛋白质序列和功能，使细菌能够表达由同一基因编码的两种RNA和蛋白质版本。然而，其患病率和意义在临床细菌设置仍不清楚。方法从尿路感染或耳部感染住院患者中分离10株大肠杆菌和7株铜绿假单胞菌。对每个分离物进行全基因组和转录组测序，然后对选定的位点进行Sanger测序。我们首次对从住院患者中分离的致病菌中的A-to-I RNA编辑进行了全面分析。我们鉴定了数十个A-to-I RNA编辑位点，包括以前未在非致病性大肠杆菌和铜绿假单胞菌菌株中报道的新位点。我们发现大肠杆菌比铜绿假单胞菌表现出更高的编辑水平和更多的编辑位点。大多数编辑位点都嵌入在保守的7碱基基序中，并且经常位于预测的茎环RNA二级结构中，这突出了序列和结构对两种被研究物种中编辑位点识别的重要性。大多数编辑事件发生在mRNA中，通常导致非同义氨基酸的变化，酪氨酸到半胱氨酸的替换显著流行。最后，我们观察到耐药菌株和敏感菌株之间的编辑模式相似，这表明在所检测物种的生物学中具有更普遍的作用。结论a -to- i RNA编辑是临床分离致病菌的一个特征。我们的发现扩大了目前在临床环境中对细菌RNA编辑的了解，并为未来的功能研究提供了一个框架。
{"title":"The landscape and regulatory determinants of A-to-I RNA editing in Escherichia coli and Pseudomonas aeruginosa isolated from patients with urinary tract and ear infections","authors":"Eyal Elias, Danielle Keidar-Friedman, Nadav Sorek, Orit Raz, Sharon Ovnat Tamir, Liam Aspit, Dan Bar Yaacov","doi":"10.1093/infdis/jiaf645","DOIUrl":"https://doi.org/10.1093/infdis/jiaf645","url":null,"abstract":"Background Adenosine-to-inosine (A-to-I) mRNA editing can alter protein sequence and function, enabling bacteria to express two RNA and protein versions encoded by the same gene. However, its prevalence and significance in clinical bacterial settings remain unclear. Methods We collected ten Escherichia coli and seven Pseudomonas aeruginosa isolates from hospitalized patients with urinary tract infections (UTI) or ear infections. Whole-genome and transcriptome sequencing were performed for each isolate, followed by Sanger sequencing for selected sites. Results We present the first comprehensive analysis of A-to-I RNA editing in pathogenic bacteria isolated from hospitalized patients. We identified dozens of A-to-I RNA editing sites, including novel sites not previously reported in non-pathogenic E. coli and P. aeruginosa strains. We found that E. coli exhibits higher editing levels and a greater number of editing sites than P. aeruginosa. Most editing sites are embedded within a conserved 7-base motif and are frequently located in predicted stem-loop RNA secondary structures, highlighting the importance of both sequence and structure for editing site recognition in both the examined species. Most editing events occur in mRNA and often result in non-synonymous amino acid changes, with a notable prevalence of tyrosine-to-cysteine substitutions. Finally, we observed that editing patterns are similar between antibiotic-resistant and sensitive isolates, suggesting a more general role in the biology of the examined species. Conclusions A-to-I RNA editing is a feature of pathogenic bacteria isolated from clinical samples. Our findings expand current knowledge of bacterial RNA editing in clinical contexts and provide a framework for future functional investigations.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145812935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
William J McCarthy,Frederick Ferguson,Lillian Gelberg
{"title":"For Optimal HIV Viral Load Reduction, Increase Intake of Gut Microbe-Friendly Foods: Comment on Palar et al.","authors":"William J McCarthy,Frederick Ferguson,Lillian Gelberg","doi":"10.1093/infdis/jiaf383","DOIUrl":"https://doi.org/10.1093/infdis/jiaf383","url":null,"abstract":"","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"20 1","pages":"e1060-e1061"},"PeriodicalIF":0.0,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145796405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The United States leads the world in biomedical innovation, with NIH-funded research driving transformative advances in cancer, HIV, and gene therapy. Yet, these breakthroughs cannot achieve their full impact in a fragmented and inequitable health system. Millions remain uninsured, preventive care is undervalued, and social determinants perpetuate life expectancy gaps. Political efforts to restrict or defund the NIH threaten progress and disproportionately harm underserved populations. Biomedical research alone cannot fix systemic failures but strengthening science while repairing care delivery systems is essential to improving population health and ensuring that innovations benefit all.
{"title":"Why Americans are Dying Younger? NIH Is Not the Problem. Our Broken Healthcare Delivery Is.","authors":"Rachel Bender Ignacio,Jade Pagkas-Bather,Gregg Gonsalves,Sara Gianella","doi":"10.1093/infdis/jiaf592","DOIUrl":"https://doi.org/10.1093/infdis/jiaf592","url":null,"abstract":"The United States leads the world in biomedical innovation, with NIH-funded research driving transformative advances in cancer, HIV, and gene therapy. Yet, these breakthroughs cannot achieve their full impact in a fragmented and inequitable health system. Millions remain uninsured, preventive care is undervalued, and social determinants perpetuate life expectancy gaps. Political efforts to restrict or defund the NIH threaten progress and disproportionately harm underserved populations. Biomedical research alone cannot fix systemic failures but strengthening science while repairing care delivery systems is essential to improving population health and ensuring that innovations benefit all.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145785846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background Sporotrichosis is a chronic, deep fungal infection of skin caused by S.schenckii. Macrophages are predominant in S.schenckii infected skin and able to phagocytize and kill the fungus. Local hyperthermia is effective to treat sporotrichosis, however, its mechanism of action remains not fully understood. Methods Using single-cell RNA sequencing of sporotrichosis lesions, coupled with in vitro and in vivo sporotrichosis models, we investigated the role of TRAF1 and NOS2. Mechanistic studies included co-immunoprecipitation, ubiquitination assays, and site-directed mutagenesis. Therapeutic mechanism of hyperthermia were evaluated in vivo and in vitro. Results We demonstrated for the first time that TRAF1 could delay the healing of sporotrichosis by inhibiting phagocytosis and killing of macrophages to S.schenckii. This effect of TRAF1 is caused by binding NOS2 to regulate its expression and enzymatic activity, through inhibition of NOS2 ubiquitination and subsequent proteasome-induced degradation. Our team's previous research has demonstrated the efficacy of hyperthermia in treating sporotrichosis. Our experiments indicate that hyperthermia can downregulate the expression of TRAF1 and NOS2 in macrophages. Conclusions We identify TRAF1-mediated stabilization of NOS2 as a key immune evasion mechanism in S. schenckii infection. Local hyperthermia represents a targeted therapy against this pathway, offering a novel strategy for enhancing the therapeutic effect of hyperthermia.
{"title":"TRAF1 Inhibits Macrophage Killing of Sporothrix schenckii by Enhancing NOS2 Expression and Activity","authors":"Congcong He, Ruiqun Qi, Yuxiao Hong, Xinghua Gao","doi":"10.1093/infdis/jiaf646","DOIUrl":"https://doi.org/10.1093/infdis/jiaf646","url":null,"abstract":"Background Sporotrichosis is a chronic, deep fungal infection of skin caused by S.schenckii. Macrophages are predominant in S.schenckii infected skin and able to phagocytize and kill the fungus. Local hyperthermia is effective to treat sporotrichosis, however, its mechanism of action remains not fully understood. Methods Using single-cell RNA sequencing of sporotrichosis lesions, coupled with in vitro and in vivo sporotrichosis models, we investigated the role of TRAF1 and NOS2. Mechanistic studies included co-immunoprecipitation, ubiquitination assays, and site-directed mutagenesis. Therapeutic mechanism of hyperthermia were evaluated in vivo and in vitro. Results We demonstrated for the first time that TRAF1 could delay the healing of sporotrichosis by inhibiting phagocytosis and killing of macrophages to S.schenckii. This effect of TRAF1 is caused by binding NOS2 to regulate its expression and enzymatic activity, through inhibition of NOS2 ubiquitination and subsequent proteasome-induced degradation. Our team's previous research has demonstrated the efficacy of hyperthermia in treating sporotrichosis. Our experiments indicate that hyperthermia can downregulate the expression of TRAF1 and NOS2 in macrophages. Conclusions We identify TRAF1-mediated stabilization of NOS2 as a key immune evasion mechanism in S. schenckii infection. Local hyperthermia represents a targeted therapy against this pathway, offering a novel strategy for enhancing the therapeutic effect of hyperthermia.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Editor's Note: Oral Ivermectin in the Treatment of Body Lice.","authors":"","doi":"10.1093/infdis/jiaf627","DOIUrl":"https://doi.org/10.1093/infdis/jiaf627","url":null,"abstract":"","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"155 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ruth A Howe, Binayak Rimal, Jay Khandelwal, Chandra Panthi, Gyanu Lamichhane
Background The incidence of non-tuberculous mycobacterial (NTM) infections has been rising and now exceeds tuberculosis in several countries. Mycobacterium avium is the most common NTM cause of chronic lung disease. Current guidelines recommend simultaneous administration of three or more antibiotics, modeled after tuberculosis treatment, but these regimens are limited by toxicity, poor adherence, and low cure rates. Importantly, unlike M. tuberculosis, M. avium is acquired from the environment rather than transmitted between humans, weakening the rationale for multidrug therapy as necessary to suppress resistance. Methods To test an alternative treatment approach, we evaluated sequential monotherapy in a validated murine model of chronic M. avium lung infection. Mice were treated with either the standard triple-drug regimen of clarithromycin, ethambutol, and rifampicin or with sequential monotherapy: clarithromycin, bedaquiline, and clofazimine, with only one drug administered at a time for four-week intervals. Lung and spleen bacterial burdens were quantified, and minimum inhibitory concentrations (MICs) were determined for isolates recovered during treatment to assess resistance emergence. Results Sequential monotherapy achieved reductions in lung bacterial burden equivalent to those of the standard multidrug regimen and prevented extrapulmonary dissemination. Notably, no increase in MICs was observed for clarithromycin, bedaquiline, or clofazimine across treatment phases, indicating that sequential monotherapy did not select for resistant clones. Conclusions These findings provide the first evidence that sequential monotherapy can deliver efficacy comparable to multidrug therapy for M. avium disease without promoting resistance. This proof-of-concept supports further investigation of sequencing strategies as a potentially more tolerable alternative to current triple-agent regimens.
{"title":"Efficacies of sequenced monotherapies of Mycobacterium avium lung infection in mouse","authors":"Ruth A Howe, Binayak Rimal, Jay Khandelwal, Chandra Panthi, Gyanu Lamichhane","doi":"10.1093/infdis/jiaf640","DOIUrl":"https://doi.org/10.1093/infdis/jiaf640","url":null,"abstract":"Background The incidence of non-tuberculous mycobacterial (NTM) infections has been rising and now exceeds tuberculosis in several countries. Mycobacterium avium is the most common NTM cause of chronic lung disease. Current guidelines recommend simultaneous administration of three or more antibiotics, modeled after tuberculosis treatment, but these regimens are limited by toxicity, poor adherence, and low cure rates. Importantly, unlike M. tuberculosis, M. avium is acquired from the environment rather than transmitted between humans, weakening the rationale for multidrug therapy as necessary to suppress resistance. Methods To test an alternative treatment approach, we evaluated sequential monotherapy in a validated murine model of chronic M. avium lung infection. Mice were treated with either the standard triple-drug regimen of clarithromycin, ethambutol, and rifampicin or with sequential monotherapy: clarithromycin, bedaquiline, and clofazimine, with only one drug administered at a time for four-week intervals. Lung and spleen bacterial burdens were quantified, and minimum inhibitory concentrations (MICs) were determined for isolates recovered during treatment to assess resistance emergence. Results Sequential monotherapy achieved reductions in lung bacterial burden equivalent to those of the standard multidrug regimen and prevented extrapulmonary dissemination. Notably, no increase in MICs was observed for clarithromycin, bedaquiline, or clofazimine across treatment phases, indicating that sequential monotherapy did not select for resistant clones. Conclusions These findings provide the first evidence that sequential monotherapy can deliver efficacy comparable to multidrug therapy for M. avium disease without promoting resistance. This proof-of-concept supports further investigation of sequencing strategies as a potentially more tolerable alternative to current triple-agent regimens.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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