Journal of Antimicrobial Chemotherapy最新文献

{"title":"Targeting autolysin ATL of Streptococcus suis: structural insights and inhibition by lanreotide acetate.","authors":"Huiming Han, Duo Zhang, Xindan Zhang, Yifei Li, Shuai Zheng, Di Zhou, Qinlong Hou, Gen Li, Shuang Li","doi":"10.1093/jac/dkag326","DOIUrl":"https://doi.org/10.1093/jac/dkag326","url":null,"abstract":"<p><strong>Background: </strong>Streptococcus suis serotype 2 (SS2) is an important zoonotic pathogen that causes severe infections in pigs and humans. Bacterial autolysins play essential roles in cell-wall remodelling and virulence; however, the structural and functional characteristics of the SS2 autolysin ATL remain poorly understood. With the increasing emergence of antimicrobial resistance, anti-virulence strategies that attenuate bacterial pathogenicity without directly inhibiting growth have attracted increasing attention.</p><p><strong>Methods: </strong>ATL domain organization was analysed bioinformatically. The catalytic domain was expressed, purified and crystallized, and its structure was determined at 1.8 Å resolution. An atl deletion mutant was generated, and ATL function was evaluated by autolysis, biofilm formation, adhesion and mouse infection assays. Lanreotide acetate was assessed for its effects on bacterial growth, ATL inhibition and anti-virulence activity in vitro and in vivo.</p><p><strong>Results: </strong>ATL contains cell-wall-binding repeats and a C-terminal Zn2+-dependent amidase domain with a His13-Glu27-His81 catalytic site. Deletion of atl did not affect bacterial growth but reduced autolysis, biofilm formation, adhesion and virulence in mice. Lanreotide acetate had a minimum inhibitory concentration (MIC) of 512 mg/L and showed no growth inhibition at sub-MIC concentrations. However, it inhibited ATL activity and reduced autolysis, biofilm formation, adhesion, barrier penetration and bacterial burden, while alleviating splenic pathology.</p><p><strong>Conclusions: </strong>ATL is a key SS2 virulence-associated autolysin. Lanreotide acetate attenuates SS2 pathogenicity by inhibiting ATL activity without suppressing bacterial growth, supporting ATL as a potential anti-virulence target.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 10","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016977","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":"Activity of the novel oral antimicrobials zoliflodacin and gepotidacin against ceftriaxone-resistant and/or multidrug-resistant Neisseria gonorrhoeae isolates from Hangzhou, China.","authors":"Wenyan Lu, Ying Fu, Xu'ai Lin, Yuefeng Rao, Magnus Unemo, Stijn van der Veen","doi":"10.1093/jac/dkag330","DOIUrl":"https://doi.org/10.1093/jac/dkag330","url":null,"abstract":"<p><strong>Objectives: </strong>The emergence of ceftriaxone-resistant Neisseria gonorrhoeae threatens the effectiveness of this last-line empirical therapy for gonorrhoea. Zoliflodacin and gepotidacin are novel oral gyrase/topoisomerase inhibitors with distinct mechanisms of action, recently US FDA-approved for treatment of uncomplicated urogenital gonorrhoea. We evaluated their in vitro activity against contemporary multidrug-resistant N. gonorrhoeae isolates from Hangzhou, China, a region with high ceftriaxone resistance.</p><p><strong>Methods: </strong>MICs of zoliflodacin and gepotidacin were determined by agar dilution for 340 clinical N. gonorrhoeae isolates collected in Hangzhou (2020-2025). Sequencing of gyrA, parC and gyrB quinolone resistance-determining regions (QRDRs) was performed.</p><p><strong>Results: </strong>All isolates were ciprofloxacin-resistant, and 23.2% were ceftriaxone-resistant. Zoliflodacin demonstrated potent activity (MIC range, 0.008-0.25 mg/L; MIC90, 0.06 mg/L). No isolate carried known GyrB target substitutions associated with increased zoliflodacin MICs (in D429 or K450), but GyrA S91F/D95G with ParC S87R was associated with slightly higher zoliflodacin wild-type MICs (P = 0.0004). Gepotidacin MICs ranged from 0.06 mg/L to 4 mg/L (MIC90, 2 mg/L); 42 isolates (12.4%) had non-susceptible MICs ≥2 mg/L. GyrA S91F/D95Y with ParC S87N and GyrA S91F/D95A with ParC D86N were associated with slightly higher gepotidacin MICs (P < 0.0001). No Spearman's rank correlation was observed between ciprofloxacin and zoliflodacin (R = 0.059) or gepotidacin (R = 0.0077) MICs.</p><p><strong>Conclusions: </strong>Zoliflodacin demonstrated potent in vitro activity and all isolates in this high-ceftriaxone-resistance setting were categorized as susceptible. Gepotidacin also showed potent activity, but 12% of isolates displayed non-susceptible MICs (≥2 mg/L). Continuous surveillance (phenotypic and genomic susceptibility) is essential when these two novel oral therapies enter clinical practice.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 10","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149080733","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":"Weight-based polymyxin B dosing for mortality and nephrotoxicity: an exploratory dose-response study.","authors":"Sung-Ching Pan, Ming-Tao Tsai, Jann-Tay Wang, Wang-Huei Sheng, Yu-Chung Chuang","doi":"10.1093/jac/dkag322","DOIUrl":"10.1093/jac/dkag322","url":null,"abstract":"<p><strong>Objectives: </strong>The optimal weight-based maintenance dose of polymyxin B is not established. We evaluated dose-response relationships for 28-day mortality and nephrotoxicity and explored a dose threshold.</p><p><strong>Methods: </strong>In this single-centre retrospective cohort, hospitalized adults received a first intravenous polymyxin B course (June 2025 to February 2026); the maintenance dose (mg/kg/day) was the exposure. Main outcomes were 28-day mortality and nephrotoxicity, defined by a creatinine-clearance criterion (≥50% fall, or  ≥ 25% with pre-existing dysfunction); renal injury was also graded by the risk, injury, failure, loss and end-stage kidney disease (RIFLE) classification. We used clinically selected dose categories (2.5, 2.75 and 3.0 mg/kg/day), exploratory classification and regression tree (CART) analysis, multivariable logistic regression and a desirability of outcome ranking.</p><p><strong>Results: </strong>The mortality cohort comprised 208 patients (28-day mortality 41.3%) and the nephrotoxicity cohort 163 (nephrotoxicity 49.7%). Mortality declined across dose categories in univariable analysis (trend P = 0.05) but was not independently associated with dose after adjustment. Nephrotoxicity increased with dose, reaching 73% at  ≥3.0 mg/kg/day; CART identified a threshold at 2.74 mg/kg/day, above which the RIFLE grade was worse (62.3% of comparisons; P = 0.006). Multivariable analysis confirmed this (adjusted odds ratio 2.60, 95% confidence interval 1.25-5.43). The desirability of outcome ranking did not differ across dose groups.</p><p><strong>Conclusions: </strong>A higher polymyxin B maintenance dose was associated with increased nephrotoxicity, particularly above approximately 2.75 mg/kg/day. The mortality estimates were imprecise and did not exclude a clinically important effect. This single-centre threshold is hypothesis-generating and requires validation before it could inform a clinical dose ceiling.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 10","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990157","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":"Acute kidney injury in Staphylococcus aureus bacteraemia: a multicentre cohort study of incidence, timing, recovery and associations with antibiotic treatment.","authors":"F S Sinkeler, I J E Kouijzer, N G L Jager, J Ten Oever, E Leegwater, J Gisolf, D Reuling, Z M Spoel, M P M Hensgens, R J Brüggemann","doi":"10.1093/jac/dkag304","DOIUrl":"10.1093/jac/dkag304","url":null,"abstract":"<p><strong>Background and objectives: </strong>Staphylococcus aureus bacteraemia (SAB) is associated with high mortality and frequent complications, including acute kidney injury (AKI). Although flucloxacillin has been associated with higher AKI rates than cefazolin, the clinical characteristics of AKI, including severity, timing, recovery and the potential influence of dosing, remain unclear.</p><p><strong>Methods: </strong>We conducted a retrospective multicentre cohort study across three hospitals in the Netherlands, including adults with SAB treated with cefazolin or flucloxacillin. AKI incidence and severity were compared using adjusted regression analyses. Time-to-event and cumulative incidence analyses were used to evaluate AKI timing and renal recovery. Among flucloxacillin-treated patients, the association between initial dose and AKI was evaluated.</p><p><strong>Results: </strong>Among 1408 patients, 483 (34.3%) developed AKI. Most AKI episodes occurred early after index blood culture (median 1.3 days), and recovery within 30 days decreased with increasing AKI severity (81.7% in Stage 1 versus 50.5% in Stage 3). AKI occurred more frequently among patients treated with flucloxacillin than cefazolin (466/1324 [35.2%] versus 17/84 [20.2%], P = 0.004). After multivariable adjustment, flucloxacillin remained associated with higher AKI risk (adjusted OR 2.37, 95% CI 1.30-4.55). Among patients with AKI, severity distribution did not differ between treatments (P = 0.599). Initial flucloxacillin dose was not associated with AKI occurrence, timing or severity.</p><p><strong>Conclusions: </strong>Flucloxacillin was associated with increased AKI risk compared with cefazolin, with most AKI episodes occurring early after index blood culture and recovery decreasing with increasing AKI severity. Lower flucloxacillin doses were not associated with reduced AKI risk, suggesting that dose reduction alone may not mitigate flucloxacillin-associated nephrotoxicity.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 10","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148873946","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":"Implementation, adoption and impact of clinical decision support system for antibiotic prescribing in primary care: a systematic review.","authors":"Racha Ibrahim, Claire Durand, Monsey Macleod, François-Xavier Lescure, Claire Amaris Hobson, Esmita Charani, Gabriel Birgand, Raheelah Ahmad, Nathan Peiffer-Smadja","doi":"10.1093/jac/dkag276","DOIUrl":"10.1093/jac/dkag276","url":null,"abstract":"<p><strong>Background: </strong>Clinical decision support systems (CDSS), computerized tools that assist clinicians in making guideline-based decisions, may support antimicrobial prescribing in primary care.</p><p><strong>Methods: </strong>Studies on CDSS implementation, use and outcomes in primary care on PubMed/MEDLINE and Embase were included up to June 2025.</p><p><strong>Results: </strong>Of the 64 full-text articles assessed, 40 were included. Most were multicentric (n = 33, 82.5%) and conducted in high-income countries (n = 33, 82.5%), and 19 were randomized controlled trials (47.5%). CDSS mainly targeted respiratory infections (n = 24, 60%) and were integrated into electronic health records in 24 studies (60%). Implementation strategies were assessed in 19 studies with almost all using a multimodal approach, most commonly involving modification of health record systems (n = 18, 45%) and audit and feedback (n = 17, 42.5%). Adoption was highly variable: among the 11 studies reporting use, CDSS were used in more than half of consultations in only five studies. Among the 32 studies assessing clinical outcomes, 17 reported reduced overall antibiotic prescribing. Barriers to CDSS use included perceptions of redundancy, time consumption, language limitations, alert fatigue, technical issues and concerns about negative impacts on patient-doctors trust.</p><p><strong>Conclusion: </strong>CDSS may improve guideline-concordant antibiotic prescribing in primary care, but wide variability in implementation and real-world adoption limits generalizability and scalability.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 10","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13531242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148864149","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":"Use of fomepizole as a novel approach for preventing aciclovir-induced neurotoxicity.","authors":"Åse Östholm, Erik Lindeman, Ylva Böttiger, Dan Eklund, Bertil Kågedal, Marie Studahl, Jan-Olov Höög, Håkan Hanberger, Anders Helldén","doi":"10.1093/jac/dkag313","DOIUrl":"10.1093/jac/dkag313","url":null,"abstract":"","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 10","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13546786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900626","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":"Reconciling differences between EUCAST 'breakpoint-defining doses' and UK national antimicrobial treatment guidelines.","authors":"Conor Jamieson, Sara E Boyd, Mandy Wootton, David M Livermore, Kieran Hand, Alasdair P Macgowan, Robin A Howe","doi":"10.1093/jac/dkag315","DOIUrl":"10.1093/jac/dkag315","url":null,"abstract":"<p><p>The British National Formulary and the NICE provide empirical treatment guidance for the management of various infections, including recommendations on antibiotic doses. In parallel, and for over 15 years, EUCAST has published details of the doses upon which their antimicrobial susceptibility breakpoints are predicated, termed here 'breakpoint-defining doses'. Recently, differences between these dosing recommendations have attracted attention, particularly since EUCAST introduced its 'susceptible, increased exposure' category of susceptibility. We discuss where and why these differences exist and how to reconcile them.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 10","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906238","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":"Assessment of Enterococcus faecalis biofilm response to amoxicillin and ciprofloxacin using a dynamic in vitro pharmacokinetic-pharmacodynamic model of catheter-associated urinary tract infection.","authors":"Desiye Tesfaye Tegegne, Paweł Jajor, Jacek Bania, Paweł Migdał, Robert Dziedzic, Błażej Poźniak","doi":"10.1093/jac/dkag311","DOIUrl":"10.1093/jac/dkag311","url":null,"abstract":"<p><strong>Background: </strong>Catheter-associated urinary tract infections (CAUTIs) are among the most common types of healthcare-associated infections. Among uropathogens, Enterococcus faecalis is particularly notable for its strong capacity to form biofilms on urinary catheters, thereby decreasing its susceptibility to antibiotics commonly used to treat CAUTIs. However, current antibiotic dosing strategies still rely on planktonic phenotypes, limiting their applicability to biofilm-associated infections. To address this limitation, a dynamic in vitro pharmacokinetic-pharmacodynamic model was developed to assess E. faecalis biofilms' response to different treatment regimens.</p><p><strong>Methods: </strong>Biofilms of model E. faecalis strains (ATCC 29212 and 54) were preformed on urinary catheters. Mature biofilms were subjected to simulated urinary dosing regimens of amoxicillin (500 mg q12h for 3 days) or ciprofloxacin (500 mg q24h for 3 days), as well as to constant antibiotic concentrations for 3 days. Viable bacterial counts and biofilm biomass were then measured at predefined timepoints, and the effects of the simulated dosing regimens were compared to those observed under constant antibiotic exposure.</p><p><strong>Results: </strong>Our findings indicate that daily ciprofloxacin demonstrated the greatest antibacterial activity, significantly surpassing the effects of constant ciprofloxacin exposure, twice-daily dosing of amoxicillin, and constant amoxicillin exposure. Although the simulated amoxicillin regimen was more effective than constant amoxicillin exposure, both achieved only moderate reductions. Notably, constant amoxicillin exposure induced biofilm formation. Ciprofloxacin exhibited markedly greater antibiofilm activity than amoxicillin against both E. faecalis strains. Among the evaluated regimens, CIP 500 mg q24h produced the most pronounced reduction in biofilm bacterial burden, achieving decreases exceeding 3 log10 cfu/cm2 in both strains after 72 h of exposure.</p><p><strong>Conclusions: </strong>The findings show that antibiotic efficacy against E. faecalis biofilms depends on the antibiotic and its dosing regimen, with fluctuating ciprofloxacin exposure producing the strongest bactericidal effect and biofilm reduction.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 10","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547859/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900689","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":"In-hospital antibiotic consumption in Lombardy, Italy (2017-2024): a retrospective analysis of regional administrative data.","authors":"Matteo Augello, Massimo Cartabia, Marina Azab, Camilla Tincati, Danilo Cereda, Olivia Leoni, Ida Fortino, Davide Mangioni, Giulia Renisi, Massimo Puoti, Pierluigi Plebani, Andrea Gori, Mauro Tettamanti, Alessandro Nobili, Alessandra Bandera, Giulia Marchetti","doi":"10.1093/jac/dkag314","DOIUrl":"10.1093/jac/dkag314","url":null,"abstract":"<p><strong>Introduction: </strong>Antimicrobial stewardship (AMS) is essential to tackle antimicrobial resistance. Antibiotic consumption (AC) surveillance provides evidence to guide AMS interventions. This study investigated in-hospital AC trends in Lombardy, Italy (2017-2024), with particular focus on the impact of COVID-19.</p><p><strong>Methods: </strong>AC was expressed as DDDs per 100 bed days (absolute AC), relative proportions of Access/Watch/Reserve antibiotics (relative AC), Access-to-Watch index, and Access-to-(Watch + Reserve) index. Analyses were stratified by ward type-medical (MUs), surgical (SUs), and intensive care units (ICUs)-and timeframes: pre-COVID-19 (01/2017-02/2020), COVID-19 onset (02-03/2020), COVID-19 (03/2020-05/2023), and post-COVID-19 (05/2023-12/2024).</p><p><strong>Results: </strong>Despite a surge in total AC in 2017-2024, relative Access AC rose while relative Watch AC declined, resulting in an increase of the Access-to-Watch and Access-to-(Watch + Reserve) indexes, except in ICUs. A transient reversal of such favourable trends was observed at COVID-19 onset. Nevertheless, the WHO 2023 target of ≥60% total AC being Access was not achieved; furthermore, Access-to-Watch and Access-to-(Watch + Reserve) indexes constantly remained <1, except for SUs. A downward trend in Access-to-Watch and Access-to-(Watch + Reserve) indexes was registered in the post-pandemic period. Reserve AC increased across time, periods and wards, exceeding the expected levels obtained using projections from pre-COVID-19 data.</p><p><strong>Conclusions: </strong>These findings highlight substantial shifts in in-hospital AC in Lombardy during the period 2017-2024, with concerning increases in Reserve antibiotics and an enduring failure to meet the 2023 WHO target of ≥60% Access antibiotics especially in MUs and ICUs, underscoring the need for reinforced AMS policies in the post-pandemic era.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 10","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13546790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900677","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":"Switching from etravirine to doravirine in people with HIV harbouring NNRTI resistance-associated mutations: the DorSwitch pilot study.","authors":"Abiu Sempere, Lorena de la Mora, Alexy Inciarte, Leire Berrocal, Ana Gonzalez-Cordón, María Mar Mosquera Cepeda, Elisa De Lazzari, María Martinez Rebollar, Montserrat Laguno, Berta Torres, Ivan Chivite, Pilar Callau, Julia Calvo, Juan Ambrosioni, Josep Mallolas, Alberto Foncillas, José María Miro, Raúl Rigo-Bonnin, Esteban Martínez, José Luis Blanco","doi":"10.1093/jac/dkag297","DOIUrl":"10.1093/jac/dkag297","url":null,"abstract":"<p><strong>Objectives: </strong>The objective of this study is to evaluate the efficacy, resistance profile, pharmacokinetics (PK) and safety of switching from etravirine to doravirine in virologically suppressed, treatment-experienced individuals with prior non-nucleoside reverse transcriptase inhibitor (NNRTI)-associated resistance mutations (NNRTI-RAMs).</p><p><strong>Methods: </strong>DorSwitch is a prospective pilot study including 13 adults with sustained virological suppression and documented historical NNRTI-RAMs. Etravirine was replaced by doravirine while maintaining the remaining antiretroviral backbone. Drug-specific resistance penalty scores were generated using the Stanford HIV Drug Resistance Database (HIVdb) algorithm. PK analyses were performed in participants receiving darunavir/cobicistat plus doravirine. Virological, immunological, metabolic and safety outcomes were assessed over 48 weeks.</p><p><strong>Results: </strong>Twelve participants completed 48 weeks of follow-up; one discontinued at Week 4 for personal reasons while virologically suppressed. All participants evaluable at Weeks 24 and 48 maintained HIV-1 RNA < 50 copies/mL, and no virological failures occurred. The median number of NNRTI-RAMs per individual was 2 (IQR 1-3). Doravirine showed lower or equal Stanford HIVdb penalty score (HIVdb-PS) than etravirine in 11/13 participants. In two cases, higher doravirine PS were driven by Y318F and G190E mutations detected in peripheral blood mononuclear cell HIV-1 DNA; both individuals remained virologically suppressed through Week 48. In seven participants receiving darunavir/cobicistat plus doravirine, trough concentrations (Cmin) were consistent with expected exposure concentrations. Total cholesterol and LDL cholesterol decreased significantly over follow-up, while body weight showed a modest, non-significant reduction. No doravirine-related serious adverse events were observed.</p><p><strong>Conclusions: </strong>In this small, highly selected pilot cohort, switching from etravirine to doravirine as part of an otherwise suppressive regimen was associated with maintenance of virological suppression through Week 48 and a more favourable predicted NNRTI resistance profile in most participants. The favourable resistance profile, safety, metabolic effects and PK findings consistent with expected exposure-particularly in combination with darunavir/cobicistat- support further evaluation of doravirine as a switch option in carefully selected individuals with prior NNRTI failure.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":"81 10","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891683","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}