Antimicrobial Agents and Chemotherapy最新文献

{"title":"Systemic absorption and safety of topical terbinafine hydrochloride 10% solution (MOB015B): a phase 1 maximal usage trial in patients with moderate-to-severe onychomycosis.","authors":"Amir Tavakkol, Janet C DuBois, Aditya K Gupta","doi":"10.1128/aac.00682-24","DOIUrl":"https://doi.org/10.1128/aac.00682-24","url":null,"abstract":"<p><p>Topical antifungals may be considered to treat onychomycosis with minimal risk of systemic side effects. In this study, we assess the safety, tolerability, systemic exposure, and pharmacokinetic characteristics of topical terbinafine hydrochloride 10% solution (MOB015B) in adults with moderate-to-severe onychomycosis. Clinically and mycologically confirmed patients with toenail onychomycosis (<i>N</i> = 20) were enrolled in this single-center, open-label study . Each patient had ≥50% involvement of both great toenails and at least four additional toenails affected. MOB015B was applied once daily to all toenails for 28 days. Blood was drawn on days 1, 14, and 28. Plasma concentrations of MOB015B after the first dose were quantifiable in all subjects by 24 h. Steady-state levels in plasma were reached by day 28. The mean systemic exposure on day 28 of 0.72 ng/mL for maximum plasma concentration (C_max) was approximately 2,000 times lower than the mean plasma level of 1.39 µg/mL seen after oral administration of 250 mg terbinafine for 28 days. Adverse events (five patients), such as headache (<i>n</i> = 3), seasonal allergy (<i>n</i> = 1), and neck pain (<i>n</i> = 1), were considered unrelated to MOB015B; no application site reactions or study discontinuations due to an adverse event were observed. MOB015B applied to all affected toenails under maximal usage conditions for 28 days demonstrated very low levels of terbinafine in plasma (C_max <1 ng/mL after 28 days), consistent with a favorable safety and tolerability profile.</p><p><strong>Clinical trials: </strong>This study is registered with ClinicalTrials.gov as NCT03244280.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999340","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":"Multicenter evaluation of activity of aztreonam in combination with avibactam, relebactam, and vaborbactam against metallo-β-lactamase-producing carbapenem-resistant gram-negative bacilli.","authors":"Lili Tao, Ashley Dahlquist, Harley Harris, Emily Jacobs, Eric Wenzler, Patricia J Simner, Romney Humphries","doi":"10.1128/aac.00693-24","DOIUrl":"https://doi.org/10.1128/aac.00693-24","url":null,"abstract":"<p><p>Treatment options for carbapenem-resistant gram-negative bacilli (CR-GNB), especially metallo-β-lactamase (MBL)-producing CR-GNB, are limited. Aztreonam (ATM) in combination with avibactam (AVI) has shown potential for treating MBL-producing carbapenem-resistant Enterobacterales (CREs) and <i>Stenotrophomonas maltophilia</i>. However, data on ATM in combination with other β-lactamase inhibitors (BLIs) are limited. We performed a multicenter study to evaluate the <i>in vitro</i> activities of ATM in combination with AVI, vaborbactam (VAB), relebactam (REL), tazobactam (TAZ) as well as with their commercially available formulations against CREs and <i>S. maltophilia</i> using broth microdilution. AVI restored ATM activity for MBL-producing CREs (ATM: 9.8% vs ATM-AVI: 78.0%) and <i>S. maltophilia</i> (ATM: 0% vs ATM-AVI: 93.3%). REL also moderately restored activity of ATM in MBL-producing CREs (ATM: 9.8% vs ATM-REL: 42.7%) and <i>S. maltophilia</i> (ATM: 0% vs ATM-REL: 68.9%). VAB and TAZ demonstrated very limited effect on the activity of ATM against CR-GNB evaluated. The combination of ATM with ceftazidime-AVI (CAZ-AVI) demonstrated maximum activity against CREs. Although ATM-CAZ-AVI is the most potent regimen available for CREs and <i>S. maltophilia</i>, ATM-IMI-REL might be a reasonable alternative.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999317","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":"Zap the clap with DNA: a novel microbicide for preventing <i>Neisseria gonorrhoeae</i> infection.","authors":"Maria A Rendon, Magdalene So","doi":"10.1128/aac.00794-24","DOIUrl":"https://doi.org/10.1128/aac.00794-24","url":null,"abstract":"<p><p>Each year, <i>Neisseria gonorrhoeae</i> (Ngo) causes over 1.5 million new infections in the United States, and >87 million worldwide. The absence of a vaccine for preventing gonorrhea, the rapid emergence of multidrug-resistant and extremely drug-resistant Ngo strains, and the limited number of antibiotics available for treating gonorrhea underscore the importance of developing new modalities for addressing Ngo infection. Here, we describe DNA-based microbicides that kill Ngo but not commensals. Previously, we showed that Ngo is killed when it takes up differentially methylated DNA with homology to its genome. We exploited this Achilles heel to develop a new class of microbicides for preventing Ngo infection. These microbicides consist of DNA molecules with specific sequences and a methylation pattern different from Ngo DNA. These DNAs kill low-passage and antibiotic-resistant clinical isolates with high efficiency but leave commensals unharmed. Equally important, the DNAs are equally effective against Ngo whether they are in buffered media or personal lubricants. These findings illustrate the potential of this new class of practical, low-cost, self-administered DNA-based microbicides for preventing Ngo transmission during sexual intercourse.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987227","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":"Pharmacokinetics and safety of GST-HG171, a novel 3CL protease inhibitor, in Chinese subjects with impaired and normal liver function.","authors":"Jing Zhou, Hong Zhang, Hong Chen, George Zhang, John Mao, Tianxiang Zhang, Yanan Tang, Wenhao Yan, Chuanjing Li, Yanhua Ding, Qinglong Jin","doi":"10.1128/aac.00539-24","DOIUrl":"10.1128/aac.00539-24","url":null,"abstract":"<p><p>GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C-like (3CL) protease inhibitor that was recently approved for treating mild to moderate coronavirus disease 2019 patients in China. Since cytochrome P450 (CYP) enzymes, primarily CYP3A, are the main metabolic enzymes of GST-HG171, hepatic impairment may affect its pharmacokinetic (PK) profile. Aiming to guide clinical dosing for patients with hepatic impairment, this study, using a non-randomized, open-label, single-dose design, assessed the impact of hepatic impairment on the PK, safety, and tolerability of GST-HG171. Patients with mild and moderate hepatic impairment along with healthy subjects were enrolled (<i>n</i> = 8 each), receiving a single oral dose of 150 mg GST-HG171, with concurrent administration of 100 mg ritonavir to sustain CYP3A inhibition before and after GST-HG171 administration (-12, 0, 12, and 24 hours). Compared to subjects with normal hepatic function, the geometric least-squares mean ratios (90% confidence intervals) for GST-HG171's maximum plasma concentration (<i>C</i>_max), area under the concentration-time curve up to the last quantifiable time (AUC_0-<i>t</i>), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC_0-∞) in subjects with mild hepatic impairment were 1.14 (0.99, 1.31), 1.07 (0.88, 1.30), and 1.07 (0.88, 1.29), respectively. For moderate hepatic impairment, the ratios were 0.87 (0.70, 1.07), 0.82 (0.61, 1.10), and 0.82 (0.61, 1.10), respectively. Hepatic impairment did not significantly alter GST-HG171's peak time (<i>T</i>_max) and elimination half-life (<i>T</i>_1/2). GST-HG171 exhibited good safety and tolerability in the study. Taken together, mild to moderate hepatic impairment minimally impacted GST-HG171 exposure, suggesting no need to adjust GST-HG171 dosage for patients with mild to moderate hepatic impairment in the clinic.Clinical TrialsRegistered at ClinicalTrials.gov (NCT06106113).</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11304707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141578774","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":"Concerns about the interpretation of treatment effects.","authors":"Shougen Sumiyoshi","doi":"10.1128/aac.00695-24","DOIUrl":"10.1128/aac.00695-24","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11304734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619171","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":"Epidemiology of <i>Clostridioides difficile</i> infection at one hospital 10 years after an outbreak of the epidemic <i>C. difficile</i> strain BI/027: changing strain prevalence, antimicrobial susceptibilities, and patient antibiotic exposures.","authors":"Jeffrey T Wieczorkiewicz, Andrew M Skinner, Adam Cheknis, Laurica A Petrella, Vanessa W Stevens, Lorinda M Wright, Dale N Gerding, Stuart Johnson","doi":"10.1128/aac.00698-24","DOIUrl":"10.1128/aac.00698-24","url":null,"abstract":"<p><p>In contrast to the epidemiology 10 years earlier at our hospital when the epidemic restriction endonuclease analysis (REA) group strain BI accounted for 72% of <i>Clostridioides difficile</i> isolates recovered from first-episode <i>C. difficile</i> infection (CDI) cases, BI represented 19% of first-episode CDI isolates in 2013-2015. Two additional REA group strains accounted for 31% of isolates (Y, 16%; DH, 12%). High-level resistance to fluoroquinolones and azithromycin was more common among BI isolates than among DH, Y, and non-BI/DH/Y isolates. Multivariable analysis revealed that BI cases were 2.47 times more likely to be associated with fluoroquinolone exposure compared to non-BI cases (95% confidence interval [CI]: 1.12-5.46). In addition, the odds of developing a CDI after third- or fourth-generation cephalosporin exposure was 2.83 times for DH cases than for non-DH cases (95% CI: 1.06-7.54). Fluoroquinolone use in the hospital decreased from 2005 to 2015 from a peak of 113 to a low of 56 antimicrobial days/1,000 patient days. In contrast, cephalosporin use increased from 42 to 81 antimicrobial days/1,000 patient days. These changes correlated with a decrease in geometric mean MIC for ciprofloxacin (61.03 to 42.65 mg/L, <i>P</i> = 0.02) and an increase in geometric mean MIC for ceftriaxone (40.87 to 86.14 mg/L, <i>P</i> < 0.01) among BI isolates. The BI strain remained resistant to fluoroquinolones, but an overall decrease in fluoroquinolone use and increase in cephalosporin use were associated with a decrease in the prevalence of BI, an increased diversity of <i>C. difficile</i> strain types, and the emergence of strains DH and Y.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11304679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141490632","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":"Zafirlukast induces DNA condensation and has bactericidal effect on replicating <i>Mycobacterium abscessus</i>.","authors":"Sanne van der Niet, Keith D Green, Irene M Schimmel, Jordy de Bakker, Bastiaan Lodder, Eric A Reits, Sylvie Garneau-Tsodikova, Nicole N van der Wel","doi":"10.1128/aac.00029-24","DOIUrl":"10.1128/aac.00029-24","url":null,"abstract":"<p><p><i>Mycobacterium abscessus</i> infections are emerging in cystic fibrosis patients, and treatment success rate in these patients is only 33% due to extreme antibiotic resistance. Thus, new treatment options are essential. An interesting target could be Lsr2, a nucleoid-associated protein involved in mycobacterial virulence. Zafirlukast is a Food and Drug Administration (FDA)-approved drug against asthma that was shown to bind Lsr2. In this study, zafirlukast treatment is shown to reduce <i>M. abscessus</i> growth, with a minimal inhibitory concentration of 16 µM and a bactericidal concentration of 64 µM in replicating bacteria only. As an initial response, DNA condensation, a known stress response of mycobacteria, occurs after 1 h of treatment with zafirlukast. During continued zafirlukast treatment, the morphology of the bacteria alters and the structural integrity of the bacteria is lost. After 4 days of treatment, reduced viability is measured in different culture media, and growth of <i>M. abscessus</i> is reduced in a dose-dependent manner. Using transmission electron microscopy, we demonstrated that the hydrophobic multilayered cell wall and periplasm are disorganized and ribosomes are reduced in size and relocalized. In summary, our data demonstrate that zafirlukast alters the morphology of <i>M. abscessus</i> and is bactericidal at 64 µM. The bactericidal concentration of zafirlukast is relatively high, and it is only effective on replicating bacteria but as zafirlukast is an FDA-approved drug, and currently used as an anti-asthma treatment, it could be an interesting drug to further study in <i>in vivo</i> experiments to determine whether it could be used as an antibiotic for <i>M. abscessus</i> infections.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11304721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141578775","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":"Reply to Sumiyoshi, \"Concerns about the interpretation of treatment effects\".","authors":"Xin Gu, Pingyu Zhou","doi":"10.1128/aac.00723-24","DOIUrl":"10.1128/aac.00723-24","url":null,"abstract":"","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11304676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619173","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":"Safety of rezafungin as a long-term treatment option in two patients with complicated fungal infections: two cases from Lecco Hospital (Italy).","authors":"Giacomo Ponta, Valentina Morena, Martina Strano, Chiara Molteni, Silvia Pontiggia, Erica Michela Cavalli, Anna Grancini, Carola Mauri, Antonella Castagna, Andrea Galanti, Stefania Piconi","doi":"10.1128/aac.00750-24","DOIUrl":"10.1128/aac.00750-24","url":null,"abstract":"<p><p>Rezafungin is an echinocandin characterized by a long elimination half-life which allows for weekly administration. It has been recently approved for the treatment of candidemia. Few data are available about the long-term use of rezafungin and its use for deep infections like endocarditis and osteomyelitis. We describe our experience with its prolonged use in two azole-resistant <i>Candida</i> infections: a case of sacral osteomyelitis and a prosthetic valve endocarditis also involving a thoracic endovascular aneurysm repair.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11304680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589505","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 survey of patient practices regarding leftover antibiotics reveals a potential source of antibiotic overuse.","authors":"Jesal Shah, Barbara W Trautner, Kiara Olmeda, Lindsey A Laytner, Fabrizia Faustinella, Michael K Paasche-Orlow, Larissa Grigoryan","doi":"10.1128/aac.00469-24","DOIUrl":"10.1128/aac.00469-24","url":null,"abstract":"<p><p>Taking leftover prescribed antibiotics without consulting a healthcare professional is problematic for the efficacy, safety, and antibiotic stewardship. We conducted a cross-sectional survey of adult patients in English and Spanish between January 2020 and June 2021 in six safety-net primary care clinics and two private emergency departments. We assessed the reasons for stopping prescribed antibiotics early and what was done with the leftover antibiotics. Additionally, we determined 1) prior leftover antibiotic use, 2) intention for future use of leftover antibiotics, and 3) sociodemographic factors. Of 564 survey respondents (median age of 51), 45% (251/564) reported a history of stopping antibiotics early, with 171/409 (42%) from safety net and 80/155 (52%) from the private clinics. The most common reason for stopping prescribed antibiotics early was \"because you felt better\" (194/251, 77%). Among survey participants, prior use of leftover antibiotics was reported by 149/564 (26%) and intention for future use of leftover antibiotics was reported by 284/564 (51%). In addition, higher education was associated with a higher likelihood of prior leftover use. Intention for future use of leftover antibiotics was more likely for those with transportation or language barriers to medical care and less likely for respondents with private insurance. Stopping prescribed antibiotics early was mostly ascribed to feeling better, and saving remaining antibiotics for future use was commonly reported. To curb nonprescription antibiotic use, all facets of the leftover antibiotic use continuum, from overprescribing to hoarding, need to be addressed.</p>","PeriodicalId":8152,"journal":{"name":"Antimicrobial Agents and Chemotherapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11304717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554043","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}