The Journal of Infectious Diseases最新文献

{"title":"Cefepime-Taniborbactam-a Novel Combination Therapy for Multidrug-Resistant Pathogens.","authors":"Richard R Watkins,Tracy L Lemonovich,Alejandro J Vila,Robert A Bonomo","doi":"10.1093/infdis/jiaf203","DOIUrl":"https://doi.org/10.1093/infdis/jiaf203","url":null,"abstract":"The ongoing spread of antimicrobial resistance has generated an urgent need for new antibiotics, especially against multidrug-resistant (MDR) gram-negative pathogens. Taniborbactam (previously VNRX-5133) is a novel bicyclic boronate β-lactamase inhibitor with potent, selective, and direct inhibitory activity against Ambler class A, B, C, and D enzymes, including serine and metallo-β-lactamases. Taniborbactam has a broader spectrum of inhibition than any other current β-lactamase inhibitor. The combination of cefepime with taniborbactam is in advanced clinical development. Investigators are studying the activity of cefepime-taniborbactam against gram-negative pathogens, including Enterobacterales species like carbapenem-resistant Klebsiella pneumoniae and MDR Pseudomonas aeruginosa with characterized carbapenem resistance mechanisms. In this review, we discuss the advances in medicinal chemistry that led to the development of cefepime-taniborbactam, the pharmacokinetics and pharmacodynamics, the antimicrobial spectrum of activity, potential uses in the clinic, and mechanisms of resistance. We propose future clinical scenarios to better explore the precise niche of this novel inhibitor combination.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932977","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":"Characterization of serotype-specific Dengue virus T cell inhibition","authors":"Jinhua Xiang, James H McLinden, Qing Chang, Micaela Fosdick, Hillel Haim, Alexander Ploss, Wesley Hottel, Nirjal Bhattarai, Tomokazu Tamura, Jiayu Zhang, Jon C D Houtman, Jack T Stapleton","doi":"10.1093/infdis/jiaf241","DOIUrl":"https://doi.org/10.1093/infdis/jiaf241","url":null,"abstract":"Background Dengue virus (DENV) serotype -2 and -3 infections are associated with more severe disease outcomes than -1 and -4, though a biological explanation for this has not been identified. Methods DENV serotype effects on human T cell activation were assessed by measuring T cell receptor (TCR)-mediated IL-2 release following TCR stimulation. DENV envelope (env) proteins were expressed in Jurkat CD4+ T cell lines and regions inhibiting TCR inhibition mapped by mutagenesis. TCR-signaling pathway inhibition was characterized by total internal reflection fluorescence microscopy and immunoblot. Reverse genetics validated env mapping results. Results T cell incubation with DENV-1 and -4 inhibited TCR signaling whereas DENV-2 and -3 did not. Inhibition did not require viral replication. DENV env protein expression inhibited TCR by interfering with activation of proximal TCR signaling events. Amino acids (aa’s) 49 to 62 of DENV 1 env were sufficient to inhibit TCR signaling, with env aa’s 55 and 66 being critical. Reverse genetics confirmed that substitution of DENV-2 and -3 aa’s 55 and 66 into DENV-1 and -4 reversed TCR inhibition, and DENV-1 aa 55 and 66 introduced into DENV-2 and -3 enhanced TCR inhibition. Conclusions DENV-2 and -3 are associated with more severe clinical disease than DENV-1 and -4; however, no biological explanation for this difference has been previously identified. We found that DENV-1 and -4 viral particles and env proteins blunt T cell responses by interfering with proximal TCR signaling while DENV-2 and -3 do not, potentially explaining DENV pathogenic outcomes in primary and secondary infection.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"1631 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920252","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":"Wastewater Measures of SARS-CoV-2 Accurately Predict Frequency of Symptomatic Infections in the Community.","authors":"Charles R Doss,Mark J Osborn,Stacey Stark,Joshua Rhein,Jacalynn Donkersgoed,Donna Budde,Shannon Champeau,Carolyn Meyer,Mason Hayden,Laura Landini,Difan Ouyang,Lappui Chung,Yi Tang,Sara Vetter,Timothy W Schacker","doi":"10.1093/infdis/jiaf242","DOIUrl":"https://doi.org/10.1093/infdis/jiaf242","url":null,"abstract":"BACKGROUNDWidespread immunity through vaccination or natural infection has altered the predictive ability of wastewater for hospitalization and mortality.METHODSBetween January 2022 and August 2024, we conducted a longitudinal observational study aimed to examine the correlation between symptomatic COVID-19 in healthcare employees and the SARS-CoV-2 wastewater community levels. Wastewater was analyzed by quantitative RT-PCR for detection of SARS-CoV-2. The employee occupational health office for Fairview Health provided deidentified data.RESULTSWe collected 215 wastewater samples from the TCWWTP over a 32-month interval. Over that period, there were 6,879 positive SARS-CoV-2 test results reported to Fairview Employee Health from individuals who lived in the wastewater catchment area. We found that SARS-CoV-2 levels in wastewater accurately predicted the subsequent COVID-19 case count the following week in the community (p = 0.001).CONCLUSIONThese data demonstrate the utility of SARS-CoV-2 wastewater surveillance as it accurately predicts the frequency of symptomatic infection in the community.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"120 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926314","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":"Trust, A Key to Counter Vaccine Hesitancy.","authors":"Samer Abdelkader,Akilah A Jefferson","doi":"10.1093/infdis/jiaf239","DOIUrl":"https://doi.org/10.1093/infdis/jiaf239","url":null,"abstract":"","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921118","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":"A plasma metabolic signature to diagnose pulmonary tuberculosis and monitor treatment response.","authors":"Jeffrey M Collins,Kidist Bobosha,Naythra Narayanan,Neel R Gandhi,Cheryl L Day,Jyothi Rengarajan,Russell R Kempker,Max S Y Lau,Mary Nellis,Nestani Tukvadze,N Sarita Shah,James C M Brust,Azhar Nizam,Nazir A Ismail,Keith D Kauffman,Shunsuke Sakai,Dean P Jones,Daniel L Barber,Thomas R Ziegler,Joel D Ernst,Henry M Blumberg,Liya Wassie,","doi":"10.1093/infdis/jiaf240","DOIUrl":"https://doi.org/10.1093/infdis/jiaf240","url":null,"abstract":"BACKGROUNDHigh-resolution metabolomics has shown promise for identifying blood-based biomarkers of tuberculosis (TB). We sought to discover a metabolic signature to detect pulmonary TB disease and monitor treatment response.METHODSPlasma from Ethiopian persons with pulmonary TB at diagnosis (n=82) was compared to household contacts with TB symptoms (n=104) and 2, 6, and 12 months after treatment initiation. Participants were divided into training and test sets for model building, with additional validation using independent cohorts from the countries of Georgia (n=89) and South Africa (n=85). Signatures were further evaluated in non-human primates infected with M. tuberculosis (Mtb).RESULTSAmong the metabolites that most significantly differed in concentration, tryptophan and retinol were significantly decreased in persons with TB disease (45.2 uM vs 62.5 uM and 4.1 uM vs 8.2 uM respectively), while kynurenine was significantly increased (2.1 uM vs 1.6 uM; q<0.0001 for all). A signature that included the kynurenine/tryptophan ratio and retinol showed excellent classification for TB disease (AUC=0.97). The signature had an AUC of 0.97 in HIV+ and 0.95 in HIV- persons with TB disease from South Africa and 0.93 in TB patients from Georgia. In Ethiopian participants, signature scores decreased after 2 (0.85 to 0.42) and 6 months of TB treatment (0.42 to 0.18; p<0.0001 for both) to similar levels as controls. Plasma retinol also declined in NHPs infected with Mtb 15-16 weeks after infection (5.9 uM vs 3.6 uM; p<0.001).CONCLUSIONSThe plasma Kyn/Trp ratio and retinol represents a promising metabolic signature that could advance TB diagnostics.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"140 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921120","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":"Time to reappraise the antibiotic treatment for methicillin-susceptible Staphylococcus aureus infective endocarditis: data from the experimental model.","authors":"C García-de-la-Mària,O Gasch,M A Cañas,J García-González,F Marco,M Hernández-Meneses,E Quintana,J Ambrosioni,C Falces,J M Tolosana,B Vidal,J M Pericas,A Perissinotti,J Llopis,A Moreno,G Cuervo,J M Miró,","doi":"10.1093/infdis/jiaf245","DOIUrl":"https://doi.org/10.1093/infdis/jiaf245","url":null,"abstract":"BACKGROUNDTraditional treatment of methicillin-susceptible Staphylococcus aureus (MSSA) native valve endocarditis is based on cloxacillin/cefazolin monotherapy. Antibiotics with high activity against MSSA such as ceftaroline and daptomycin have been marketed last years, but there are no clinical trials evaluating them as monotherapy or combination therapy in patients with MSSA endocarditis.OBJECTIVESTo compare the efficacy of cloxacillin, ceftaroline and daptomycin monotherapies and daptomycin combinations with beta-lactams in a rabbit model of MSSA endocarditis.METHODSEndocarditis was induced in rabbits using two strains of MSSA. After 24h of infection, they received human-like doses of cloxacillin, ceftaroline or daptomycin or combinations of daptomycin plus either cloxacillin or ceftaroline. Isolates recovered from vegetation, spleen and kidney were retested for daptomycin non-susceptibility (DNS) post-treatment.RESULTSMSSA vancomycin MIC did not influence the efficacy of any antibiotic treatment. Cloxacillin, ceftaroline and daptomycin had similar activity (25-50%) in sterilizing vegetations. However, 13% of rabbits treated with daptomycin developed DNS. The addition of daptomycin to cloxacillin or ceftaroline was synergistic and bactericidal, showing significantly more activity and higher rates of sterile vegetations (≥90%) than any monotherapy Combinations also showed better activity in spleens and kidneys compared with daptomycin monotherapy and prevented the development of DNS in all tissues. There were no differences between the two daptomycin combinations.CONCLUSIONSIn the MSSA experimental endocarditis model, daptomycin combinations with beta-lactams had significantly better activity than either their monotherapies in sterilizing valve vegetations and preventing DNS development. These findings support their use in clinical practice and to perform clinical trials.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"96 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921121","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":"Tackling HIV Drug Resistance in the Philippines: A Call to Action.","authors":"Jeff Clyde G Corpuz","doi":"10.1093/infdis/jiaf236","DOIUrl":"https://doi.org/10.1093/infdis/jiaf236","url":null,"abstract":"","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921122","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":"Safety, Tolerability, and Pharmacokinetics of Once-Monthly Oral Islatravir: a Phase 2a Study in Participants at Low Risk for Acquiring HIV-1.","authors":"Sharon L Hillier,Linda-Gail Bekker,Sharon A Riddler,Craig W Hendrix,Sharlaa Badal-Faesen,Pippa Macdonald,Gonasagrie Nair,Johannes Lombaard,Yoseph Caraco,Avivit Peer,Munjal Patel,Ryan Vargo,Brenda Homony,Katherine Nedrow,Barbara Evans,Prachi Wickremasingha,Yun-Ping Zhou,Valerie Teal,Peggy Hwang,Ciaran McMullan,Keith D Kaufman,Michael N Robertson,Rebeca M Plank","doi":"10.1093/infdis/jiaf222","DOIUrl":"https://doi.org/10.1093/infdis/jiaf222","url":null,"abstract":"BACKGROUNDIslatravir, a nucleoside reverse transcriptase translocation inhibitor, exhibits high potency against HIV-1, with a long intracellular half-life. The safety, tolerability, and pharmacokinetics of once-monthly oral islatravir were evaluated in adults at low risk of acquiring HIV-1.METHODSIn this double-blind placebo-controlled trial, participants were randomized 2:2:1 to receive 6 once-monthly doses of islatravir 60 mg, islatravir 120 mg, or placebo. Objectives included assessing safety, tolerability, and pharmacokinetic profiles of islatravir in plasma and its active metabolite, islatravir-triphosphate, in peripheral blood mononuclear cells (PBMCs).RESULTSOf 242 participants (islatravir 60 mg, n=97; islatravir 120 mg, n=97; placebo, n=48), most were aged <45 years (90.1%), female (67.4%), and White (52.9%). Proportions of participants experiencing ≥1 adverse event (AE) were similar in islatravir (60-mg: 68.0%; 120-mg: 64.9%) and placebo arms (75.0%). AEs were generally mild-moderate, with infection-related AEs comparable across arms. Lymphocyte count decreased in the islatravir arms, with mean percent changes of -21.3±20.1% (60-mg) and -35.6±22.8% (120-mg) vs +4.4±25.9% (placebo) at week 24. Median intracellular PBMC islatravir-triphosphate concentrations remained above the prespecified pharmacokinetics threshold for HIV-1 prophylaxis (0.050 pmol/106 cells) through 4 weeks after the first dose and ≥8 weeks after the last dose.CONCLUSIONSOral islatravir 60 mg and 120 mg once monthly demonstrated similar tolerability and AE profiles to placebo, except for dose-dependent decreases in total lymphocyte counts. A partial recovery in total lymphocyte counts was observed. In most participants, both islatravir doses achieved PBMC islatravir-triphosphate exposure levels projected to be effective for once-monthly oral HIV-1 pre-exposure prophylaxis.CLINICAL TRIALS REGISTRATIONwww.clinicaltrials.gov, NCT04003103.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915105","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":"Heterogeneous antiretroviral drug exposure in male and female genital tract tissues","authors":"Elias P Rosen, Nicole White, Craig Sykes, Lourdes Adamson, Paul Luciw, Ashlyn Norris, Yuri Fedoriw, Angela D M Kashuba","doi":"10.1093/infdis/jiaf225","DOIUrl":"https://doi.org/10.1093/infdis/jiaf225","url":null,"abstract":"Background Cell-associated HIV has been found in tissues whose architecture can limit antiretroviral drug penetration, including the genital tract. Methods In healthy and SHIV-infected rhesus macaques dosed for 10 days with four-drug combination therapy, we evaluated the spatial distribution of six antiretroviral drugs (ARVs) within the male and female genital tract by mass spectrometry imaging (MSI). We also measured drug transporter gene expression in these tissues to determine their influence of in situ variability of ARV exposure. Results Through MSI, drug-dependent, heterogeneous ARV accumulation was observed with preferential accumulation in capsular and epithelial spaces for male and female genital tract tissues, respectively. ARVs were primarily detected as single drug exposure across genital tract tissue sections, with the proportion of tissue where any single ARV was detected (median (range): Vagina =58% (5.1-82.3%); Testis = 16.6% (3.9-88.4%)) exceeded detection of any two (Vagina =13.8% (0.2-30.8%); Testis = 0.9% (0.0-72.8%)) or any three colocalized ARVs (Vagina =1.8% (0.0-2.5%); Testis = 0.0% (0.0-43.1%)). Most 59.7% (45.8-90.1%) of the ARV response in vaginal tissue was found to be colocalized with the blood marker heme, suggesting its origin was from the vasculature rather than parenchymal tissue, while interindividual variability in ARV penetration was higher in testis. Conclusion In both female and male genital tract tissues, ARV penetration did not follow simple trends based solely on molecular size or degree of protein binding and the combination of MSI and drug transporter expression suggest that multiple mechanisms including drug transporters participate in determining local accumulation within this tissue.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910219","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":"The Impact of Diet on Clostridioides difficile Infection: A Review","authors":"Melissa Castro, Heidi J Silver, Keith Hazleton, Catherine Lozupone, Maribeth R Nicholson","doi":"10.1093/infdis/jiaf233","DOIUrl":"https://doi.org/10.1093/infdis/jiaf233","url":null,"abstract":"Clostridioides difficile poses a significant public health challenge as it is the leading cause of antibiotic-associated diarrhea and is associated with significant morbidity and mortality. C. difficile’s metabolism and pathogenesis are strongly influenced by nutrient availability from the host and gut commensals. This has caused increasing interest in dietary intake and diet-derived metabolites’ role in C. difficile infection (CDI). Although much of the data currently originates from animal models, there is growing evidence of the ability of diet to impact CDI-related outcomes. This review aims to enrich the understanding of dietary components that impact C. difficile metabolism and pathogenesis, as well as provide limitations in the current science to support future inquiry. Without a better understanding of the influence of diet on CDI in the human host, we lack a non-pharmacologic approach to prevent and treat this important condition.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"99 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910400","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}