Journal of Antimicrobial Chemotherapy最新文献

{"title":"Comparing serotype coverage of pneumococcal vaccines with PCV21 (V116), a new 21-valent conjugate pneumococcal vaccine, and the epidemiology of its eight unique Streptococcus pneumoniae serotypes (15A, 15C, 16F, 23A, 23B, 24F, 31 and 35B) causing invasive pneumococcal disease in adult patients in Canada: SAVE study, 2018-21.","authors":"John J Schellenberg, Heather J Adam, Melanie R Baxter, James A Karlowsky, Alyssa R Golden, Irene Martin, George G Zhanel","doi":"10.1093/jac/dkaf085","DOIUrl":"10.1093/jac/dkaf085","url":null,"abstract":"<p><strong>Background: </strong>V116 is a novel 21-valent pneumococcal conjugate vaccine (PCV) intended for use in adults.</p><p><strong>Objectives: </strong>To estimate current V116 serotype coverage in adult patients in Canada compared with PCV15, PCV20 and PPSV23 vaccines, and to describe isolate demographics for the eight unique serotypes (15A, 15C, 16F, 23A, 23B, 24F, 31 and 35B) covered by V116.</p><p><strong>Methods: </strong>From 2018 to 2021 inclusive, the SAVE study collected 5854 invasive pneumococcal disease (IPD) isolates as part of a collaboration between the Canadian Antimicrobial Resistance Alliance and the Public Health Agency of Canada-National Microbiology Laboratory. Serotypes were determined by Quellung reaction and antimicrobial susceptibility testing performed using the CLSI broth microdilution method.</p><p><strong>Results: </strong>For adult patients (≥18 years), adults 50-64 years and adults ≥65 years, respectively, IPD isolate coverage was PCV15 (42.7%; 41.0%, 39.8%), PCV20 (59.0%; 60.2%, 52.2%), PPSV23 (70.4%; 75.1%, 60.0%), V116 (78.9%; 76.3%, 81.5%) and V116 plus PCV20 (92.2%; 91.0%, 89.3%). The eight unique V116 serotypes accounted for 19.7% and 26.8% of IPD isolates from adults and adults ≥65 years, respectively. Among the eight unique V116 serotypes, 15A and 23A demonstrated the highest rates of MDR (17.0% and 10.2%, respectively); 6.7% of 15A isolates were XDR.</p><p><strong>Conclusions: </strong>V116 provided significantly (P < 0.05) greater coverage than PCV15, PCV20 and PPSV23 for adults, including older adults, across all Canadian geographic regions, and against IPD isolates with common antimicrobial resistance phenotypes, including MDR. The eight unique V116 serotypes accounted for a higher proportion of IPD isolate serotypes in patients aged ≥65 years than younger adults.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"1377-1385"},"PeriodicalIF":3.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700446","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":"Cellular pharmacology of tenofovir alafenamide and emtricitabine in neutrophils and platelets in people with and without HIV.","authors":"Vincent A Mainella, Brian Branchford, Travis Nemkov, Seth Hosford, Ryan P Coyle, Bethany Johnson, Ye Ji Choi, Martin Williams, Jia-Hua Zheng, Lane Bushman, Jennifer J Kiser, Peter L Anderson, Kristina M Brooks","doi":"10.1093/jac/dkaf052","DOIUrl":"10.1093/jac/dkaf052","url":null,"abstract":"<p><strong>Background: </strong>Previous studies have primarily focused on nucleos(t)ide reverse transcriptase inhibitor pharmacology in peripheral blood mononuclear cells (PBMCs) and erythrocytes via dried blood spots (DBS), but not other major blood cells.</p><p><strong>Objectives: </strong>Our objectives were to describe and compare the concentrations of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in DBS, PBMCs, neutrophils, and platelets in people with HIV (PWH) and people without HIV (PWOH).</p><p><strong>Methods: </strong>DBS, PBMCs, neutrophils, and platelets were isolated from whole blood drawn from PWH and PWOH receiving tenofovir alafenamide and emtricitabine. TFV-DP and FTC-TP concentrations were quantified using LC-MS/MS in each cell type. Linear regression models controlled for time on drug, adherence, and time since last dose, where applicable, to determine geometric mean percent differences (95% confidence interval) by HIV status and estimated half-lives.</p><p><strong>Results: </strong>Data were available in 13 PWH (96% male) and 30 PWOH (53% male). Compared with PWOH, TFV-DP in DBS was 48.9% (15.6%, 91.9%) higher and FTC-TP in platelets was 36.3% (4.5%, 77.7%) higher; TFV-DP in platelets also trended higher [43.5% (-3.24%, 113%)]. No other cell types significantly differed by HIV status. TFV-DP and FTC-TP demonstrated the longest half-lives in neutrophils, followed by PBMCs and then platelets. After normalizing to cell volume, both drugs accumulated from greatest to least in PBMCs, neutrophils, platelets, and erythrocytes across both PWH and PWOH.</p><p><strong>Conclusions: </strong>Our findings highlight differential drug disposition across cell types that also vary by serostatus in DBS and platelets. The mechanisms and implications of these findings require additional research.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"1224-1232"},"PeriodicalIF":3.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556878","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":"Resistance profiles of carbapenemase-producing Enterobacterales in a large centre in England: are we already losing cefiderocol?-authors' response.","authors":"Ioannis Baltas, Trupti Patel, Ana Lima Soares","doi":"10.1093/jac/dkaf075","DOIUrl":"10.1093/jac/dkaf075","url":null,"abstract":"","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"1468-1469"},"PeriodicalIF":3.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604783","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":"GP or ChatGPT? Ability of large language models (LLMs) to support general practitioners when prescribing antibiotics.","authors":"Oanh Ngoc Nguyen, Doaa Amin, James Bennett, Øystein Hetlevik, Sara Malik, Andrew Tout, Heike Vornhagen, Akke Vellinga","doi":"10.1093/jac/dkaf077","DOIUrl":"10.1093/jac/dkaf077","url":null,"abstract":"<p><strong>Introduction: </strong>Large language models (LLMs) are becoming ubiquitous and widely implemented. LLMs could also be used for diagnosis and treatment. National antibiotic prescribing guidelines are customized and informed by local laboratory data on antimicrobial resistance.</p><p><strong>Methods: </strong>Based on 24 vignettes with information on type of infection, gender, age group and comorbidities, GPs and LLMs were prompted to provide a treatment. Four countries (Ireland, UK, USA and Norway) were included and a GP from each country and six LLMs (ChatGPT, Gemini, Copilot, Mistral AI, Claude and Llama 3.1) were provided with the vignettes, including their location (country). Responses were compared with the country's national prescribing guidelines. In addition, limitations of LLMs such as hallucination, toxicity and data leakage were assessed.</p><p><strong>Results: </strong>GPs' answers to the vignettes showed high accuracy in relation to diagnosis (96%-100%) and yes/no antibiotic prescribing (83%-92%). GPs referenced (100%) and prescribed (58%-92%) according to national guidelines, but dose/duration of treatment was less accurate (50%-75%). Overall, the GPs' accuracy had a mean of 74%. LLMs scored high in relation to diagnosis (92%-100%), antibiotic prescribing (88%-100%) and the choice of antibiotic (59%-100%) but correct referencing often failed (38%-96%), in particular for the Norwegian guidelines (0%-13%). Data leakage was shown to be an issue as personal information was repeated in the models' responses to the vignettes.</p><p><strong>Conclusions: </strong>LLMs may be safe to guide antibiotic prescribing in general practice. However, to interpret vignettes, apply national guidelines and prescribe the right dose and duration, GPs remain best placed.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"1324-1330"},"PeriodicalIF":3.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624583","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":"Exceedingly high levels of tetracycline resistance in Neisseria gonorrhoeae in eight WHO Enhanced Gonococcal Antimicrobial Surveillance Programme countries in three WHO regions, 2021-2024-doxycycline post-exposure prophylaxis will unlikely impact gonorrhoea burdens.","authors":"Daniel Schröder, Thitima Cherdtrakulkiat, Le Huu Doanh, Daniel Golparian, Lon Say Heng, Irving Hoffman, Susanne Jacobsson, Manuel C Jamoralin, Francis Kakooza, Rossaphorn Kittiyaowamarn, Peter Kyambadde, Venessa Maseko, Mitch Matoga, Etienne Müller, Thuy Thi Phan Nguyen, Vichea Ouk, Vivi Setiawaty, Sonia B Sia, Verawati Sulaiman, Mot Virak, Nguyen Thi Thuy Van, Teodora Wi, Ismael Maatouk, Magnus Unemo","doi":"10.1093/jac/dkaf066","DOIUrl":"10.1093/jac/dkaf066","url":null,"abstract":"<p><strong>Objectives: </strong>Doxycycline post-exposure prophylaxis (doxycycline-PEP) can reduce incident cases of syphilis, chlamydia and possibly gonorrhoea especially among men who have sex with men with recent bacterial sexually transmitted infections (STIs). Owing to potential implementation of doxycycline-PEP internationally, global tetracycline/doxycycline resistance data for contemporary Neisseria gonorrhoeae isolates has become imperative. We report tetracycline resistance data for gonococcal isolates (n = 2993) from eight WHO Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP) countries in three WHO regions in 2021-2024, i.e. to estimate potential impact of doxycycline-PEP on the incident gonorrhoea cases in these WHO EGASP countries.</p><p><strong>Methods: </strong>WHO EGASP isolates cultured from men with urethral discharge in Cambodia (n = 482), Indonesia (n = 101), Malawi (n = 121), The Philippines (n = 843), South Africa (n = 597), Thailand (n = 250), Uganda (n = 350) and Vietnam (n = 249) in 2021-2024 were examined. MICs (mg/L) of tetracycline were determined using Etest.</p><p><strong>Results: </strong>The tetracycline resistance (range) using the current EUCAST (MIC > 0.5 mg/L) and CLSI (MIC > 1 mg/L) clinical resistance breakpoints in the eight WHO EGASP countries was 92.2% (83.5%-99.6%) and 80.6% (66.3%-98.6%), respectively. Using a previous minocycline-PEP resistance breakpoint (MIC > 2 mg/L) and breakpoint for high-level plasmid (tetM)-mediated tetracycline resistance (MIC > 8 mg/L), the tetracycline resistance (range) was 77.3% (47.4%-98.6%) and 74.3% (31.3%-98.6%), respectively.</p><p><strong>Conclusions: </strong>The exceedingly high levels of gonococcal tetracycline resistance (independent of resistance breakpoint used) in the eight WHO EGASP countries elucidate that doxycycline-PEP will unlikely significantly reduce the gonorrhoea cases in these countries. Furthermore, doxycycline-PEP might rapidly select for additional gonococcal strains with tetracycline resistance (low- and high-level) and MDR/XDR strains, i.e. because these strains are mostly resistant to tetracycline.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"1291-1295"},"PeriodicalIF":3.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657026","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":"In vitro activity of ceftolozane/tazobactam, ceftazidime/avibactam and cefiderocol against clinical isolates of non-aeruginosa Pseudomonas.","authors":"Lucie Thene, Pauline Floch, Camille V Chagneau, Damien Dubois, Clémence Massip","doi":"10.1093/jac/dkaf067","DOIUrl":"10.1093/jac/dkaf067","url":null,"abstract":"<p><strong>Background: </strong>Although less virulent than Pseudomonas aeruginosa, non-aeruginosa Pseudomonas (NAP) are opportunistic pathogens that cause invasive infections, mainly in immunosuppressed or intensive care patients. MDR strains of NAP are increasingly isolated, especially MBL-producing isolates.</p><p><strong>Objectives: </strong>We evaluated the activity of cefiderocol, ceftazidime/avibactam and ceftolozane/tazobactam against a collection of clinical isolates of NAP, which was voluntarily enriched with resistant strains.</p><p><strong>Methods: </strong>We retrospectively determined the MICs of cefiderocol, ceftazidime/avibactam and ceftolozane/tazobactam in 71 NAP clinical isolates. Most isolates of our collection were not susceptible to meropenem (75%) or ceftazidime (45%).</p><p><strong>Results: </strong>Among the first-line β-lactam-resistant isolates, the strains for which no carbapenemase was detected were susceptible to ceftolozane/tazobactam or ceftazidime/avibactam, except for one isolate. These latter associations were more active against P. fluorescens isolates than against other NAP. Most isolates (94%) of our collection were susceptible to cefiderocol, with a median MIC of 0.25 mg/L. In particular, the 19 carbapenemase-producing strains, including 15 VIM-producing strains, were susceptible to cefiderocol. Cefiderocol MICs were higher for P. fluorescens complex isolates (MIC50 = 2 mg/L) than for P. putida complex isolates (MIC50 = 0.25 mg/L). Resistance to cefiderocol was detected in only four isolates, of which three P. fluorescens complex isolates remained susceptible to ceftolozane/tazobactam and ceftazidime/avibactam.</p><p><strong>Conclusions: </strong>Ceftolozane/tazobactam and ceftazidime/avibactam may be of interest as second-line β-lactams against non-carbapenemase-producing strains. Cefiderocol was highly active against NAP of our collection, especially MBL-producing isolates. Further studies are needed to correlate in vitro susceptibility of NAP to cefiderocol and clinical responses.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"1296-1301"},"PeriodicalIF":3.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656960","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":"Population pharmacokinetics of aciclovir and its major metabolite 9-carboxymethoxymethylguanine and safety profile of valaciclovir in early liver transplant recipients.","authors":"Benjamin Kably, Mathilde Briard, Claire Francoz, Olivier Roux, Nadhira Houhou, Vincent Mackiewicz, Gilles Peytavin, Francois Durand, Minh P Lê","doi":"10.1093/jac/dkaf070","DOIUrl":"10.1093/jac/dkaf070","url":null,"abstract":"<p><strong>Background: </strong>Valaciclovir is frequently prescribed for cytomegalovirus infection prophylaxis. Its major metabolite 9-carboxymethoxymethylguanine (9-CMMG), when accumulated in renally impaired patients, is neurotoxic. Its synthesis involves enzymes that could be impacted in liver transplant recipients. This retrospective study aimed to describe the pharmacokinetic (PK) and safety profile of aciclovir and 9-CMMG early after liver transplantation in patients receiving valaciclovir prophylaxis.</p><p><strong>Methods: </strong>Consecutive (ideally five) blood samples were drawn. Plasma concentrations of aciclovir/9-CMMG were quantified by UPLC-MS/MS. Medical data were collected from digital records. A joint population PK model for aciclovir/9-CMMG was developed (Monolix 2023R1). Monte Carlo simulations were used to estimate Cmin and AUC0-24.</p><p><strong>Results: </strong>Fifty patients (21 women) in the postoperative phase of liver transplantation were enrolled, with median age of 56.0 years and median weight of 69.5 kg; 255 samples were collected 19.0 days after transplantation. No drug-drug interaction was reported. A one-compartment model with first-order absorption best described the pharmacokinetics (PK). Covariate analysis showed that aciclovir and 9-CMMG clearances correlated with estimated glomerular filtration rate (eGFR). In normorenal patients, receiving valaciclovir 2000 mg q8h, estimated AUC0-24 values were 44.8 and 13.3 mg·h/L for aciclovir and 9-CMMG, respectively. The median estimated metabolic ratio of AUC0-24 (9-CMMG/aciclovir) was 30.4% and 129.9% for patients with >90 and <30 mL/min/1.73 m2 eGFR, respectively. There were no valaciclovir-related adverse events during hospitalization.</p><p><strong>Conclusions: </strong>This model allowed the PK and basal metabolic ratio of aciclovir and 9-CMMG in early liver transplantation to be defined. The correlation with renal function suggests important implications for therapeutic drug monitoring of these compounds, which will need confirmation in different cohorts.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"1302-1308"},"PeriodicalIF":3.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742842","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":"Viral suppression after failure of PI-based ART among adolescents and youths with and without drug resistance mutations: a longitudinal analysis in Tanzania.","authors":"Joan Rugemalila, Robert Ndege, Peter Kunambi, Siraji Shabani, Veryeh Sambu, Anath Rwebemberwa, Samuel Kalluvya, Bruno Sunguya, Tumaini Nagu, Said Aboud","doi":"10.1093/jac/dkaf125","DOIUrl":"https://doi.org/10.1093/jac/dkaf125","url":null,"abstract":"<p><strong>Background: </strong>People living with HIV (PLHIV) who fail first-line ART have a higher risk of failing subsequent ART. We examined viral suppression (VS) among adolescents and youths (AY) failing PI ART in Tanzania.</p><p><strong>Methods: </strong>We conducted a retrospective study nested within a national third-line cohort of PLHIV. We analysed data of 147 AY (aged 10-24 years) with failure of PI-based ART between 2020 and 2022 who were followed for 12 months to assess for VS. Descriptive statistics were summarized by demographics and clinical characteristics, and we used logistic regression to assess factors associated with virological failure (VF) and drug resistance mutations (DRMs).</p><p><strong>Results: </strong>More than 40% of 147 participants had HIV subtype A, 52% (76/147) harboured major PI DRMs and 35% had NRTI mutations. A PI regimen at ART initiation was associated with a major PI DRM adjusted relative risk (aRR) of 1.66 (95% CI: 1.13-2.44; P = 0.010). Among participants with major PI DRMs, 12.2% had intermediate to high levels of resistance to lopinavir and atazanavir, and 2.1% to darunavir, respectively. V82A was the most frequent PI DRM; NRTI mutations included thymidine analogue mutations and absent K65R. VS occurred in 65% of AY who had PI DRMs compared with 45% of those without DRMs; this difference was not statistically significant.</p><p><strong>Conclusions: </strong>More than half of AY who had PI DRMs had a higher proportion of early VS (65%) compared with those without DRMs (45%). Optimal viral load monitoring, adherence intensification and routine drug resistance testing are key strategies to improve VS.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144000292","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":"In vitro and in vivo antibacterial activity, resistance analysis and molecular docking study of pleuromutilin derivatives against Streptococcus suis.","authors":"Sujuan Wu, Lu Zhang, Xinyue Luo, Changcheng Lin, Peng Wan, Honghao Huang, Yixing Lu, Youzhi Tang, Zhenling Zeng","doi":"10.1093/jac/dkaf064","DOIUrl":"10.1093/jac/dkaf064","url":null,"abstract":"<p><strong>Objectives: </strong>To evaluate the in vitro and in vivo antimicrobial activity of pleuromutilin derivatives modified with C14 side-chain against Streptococcus suis.</p><p><strong>Methods: </strong>To determine the minimum inhibitory concentrations (MICs) of 268 pleuromutilin derivatives with C14 side-chain modifications against S. suis ATCC 43 765 using the broth dilution method. Derivative B43, B49, B52, B53 and B54, which exhibited better antimicrobial activity, were selected for further investigation of their in vitro antibacterial effect, cytotoxicity, and in vivo antibacterial effect.</p><p><strong>Results: </strong>Determination activity of five derivatives against clinical strains (n = 37), as well as growth and time-killing curves. Those experiments showed that all the five derivatives had good activity against S. suis in vitro. Resistance-inducing assays demonstrated that, except for B43, the derivatives had similar abilities to induce resistance to tiamulin. In addition, the five derivatives did not have erythrocyte haemolytic toxicity (0.25-16 mg/L) and cytotoxicity (1.25-80 mg/L). In the mouse thigh infection model, the derivative of B49 exhibited superior antibacterial efficacy. About 40 mg/kg B49 had good activity and improved the survival rate of mice by 33.3% in the S. suis mouse peritonitis model. Molecular docking study and scanning electron microscopy revealed that B49 can effectively bind to the active site of the 50S ribosome and disrupt cell membranes.</p><p><strong>Conclusions: </strong>A total of 68.66% of the 268 C14 side-chain modified pleuromutilin derivatives showed potent activity against S. suis. Among them, B49 showed good in vitro and in vivo antimicrobial effects against S. suis, indicating that B49 can be intensively studied as an antimicrobial candidate compound.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"1274-1286"},"PeriodicalIF":3.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143624584","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":"Repurposing tafenoquine as a potent antifungal agent against Candida haemulonii sensu stricto.","authors":"Larissa Rodrigues Pimentel, Fabíola Lucini, Gabrieli Argueiro da Silva, Simone Simionatto, Luana Rossato","doi":"10.1093/jac/dkaf054","DOIUrl":"10.1093/jac/dkaf054","url":null,"abstract":"<p><strong>Background: </strong>The rise in fungal infections caused by multidrug-resistant pathogens like Candida haemulonii sensu stricto presents a significant global health challenge. The common resistance to current treatments underscores the urgency to explore alternative therapeutic strategies, including drug repurposing.</p><p><strong>Objectives: </strong>To assess the potential of repurposing tafenoquine, an antimalarial agent, for antifungal use against C. haemulonii sensu stricto.</p><p><strong>Methods: </strong>The efficacy of tafenoquine was tested using in vitro assays for minimum inhibitory concentration (MIC), minimum fungicidal concentration, biofilm inhibition, cell damage, cell membrane integrity, nucleotide leakage, sorbitol protection assay, and efflux pump inhibition. The compound's cytotoxicity was assessed through a haemolysis assay, and in vivo safety and efficacy were tested using Tenebrio molitor larvae.</p><p><strong>Results: </strong>Tafenoquine exhibited potent fungicidal activity against C. haemulonii sensu stricto with an MIC of 4 mg/L and significantly inhibited biofilm formation by 60.63%. Tafenoquine also impaired mitochondrial functionality, leading to compromised cellular respiration. Despite these effects, tafenoquine did not cause significant protein leakage, indicating a distinct mechanism from membrane-targeting agents. In vivo study confirmed tafenoquine's non-toxic profile with no observed haemolysis or acute toxicity in the T. molitor model. During antifungal treatment with tafenoquine, a survival rate of approximately 60% was observed after 3 days.</p><p><strong>Conclusions: </strong>The findings of this study highlight tafenoquine's potential as a promising candidate for antifungal drug repurposing, especially against C. haemulonii sensu stricto. Its effectiveness in inhibiting fungal growth and biofilm formation underscores its viability for further clinical development as a novel antifungal therapy.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":" ","pages":"1233-1240"},"PeriodicalIF":3.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483218","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}