首页 > 最新文献

Journal of Antimicrobial Chemotherapy最新文献

英文 中文
Differential frequency of persister cells in clinically derived isolates of Pseudomonas aeruginosa after exposure to cefiderocol and ceftolozane/tazobactam. 临床分离的铜绿假单胞菌在暴露于头孢克洛和头孢唑烷/他唑巴坦后,其宿主细胞的频率不同。
IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES Pub Date : 2024-10-24 DOI: 10.1093/jac/dkae346
Aliaa Fouad, Samantha E Nicolau, Pranita D Tamma, Patricia J Simner, David P Nicolau, Christian M Gill

Background: Bacterial persistence is a phenomenon whereby a subpopulation of bacteria survive high concentrations of an active antibiotic in the absence of phenotypic alterations. Persisters are associated with chronic and recurrent infections for pathogens including Pseudomonas aeruginosa. Understanding persister profiles of newer antibiotics such as cefiderocol and ceftolozane/tazobactam against P. aeruginosa is warranted as these agents generally target difficult-to-treat infections.

Methods: Persister formation was assessed using in vitro assays against nine clinical P. aeruginosa isolates exposed to cefiderocol or ceftolozane/tazobactam. Quantitative persister assays were performed using a stationary phase of bacteria challenged with 10-fold MIC drug concentrations. Persisters were quantitated as the percent persisters at 24 h and the log ratio (LR) difference in AUC for cfu for each antibiotic alone compared with growth control. The tolerance disc test (TDtest) was used to qualitatively detect persisters.

Results: Percent persisters at 24 h was lower with cefiderocol compared with ceftolozane/tazobactam for six of the nine tested isolates. Eight of the nine isolates had higher reduction in LR for cefiderocol groups, suggesting an overall higher and more rapid bacterial reduction in cefiderocol groups. For cefiderocol, five of the nine tested isolates lacked regrowth after replacement with glucose disc, suggesting no persistence via the TDtest. For ceftolozane/tazobactam, three isolates lacked persister formation.

Conclusions: Cefiderocol resulted in less bacterial persistence relative to ceftolozane/tazobactam against nine clinical P. aeruginosa isolates. Cefiderocol's siderophore mechanism may be advantageous over ceftolozane/tazobactam through enhanced anti-persister effects. Clinical correlation of these findings is warranted as persisters can lead to antibiotic resistance and treatment failure.

背景:细菌持久性是指细菌亚群在没有表型改变的情况下,在高浓度活性抗生素的作用下存活下来的现象。持久菌与包括铜绿假单胞菌在内的病原体的慢性和复发性感染有关。有必要了解头孢哌酮和头孢唑烷/他唑巴坦等新型抗生素针对铜绿假单胞菌的持久菌特征,因为这些药物通常针对难以治疗的感染:方法:针对暴露于头孢啶醇或头孢唑烷/他唑巴坦的九个临床铜绿假单胞菌分离物,采用体外试验评估了持久菌的形成。采用 10 倍 MIC 药物浓度的细菌静止期进行定量宿主检测。宿主定量为 24 小时后的宿主百分比,以及每种抗生素单独使用时与生长对照组相比的菌落总数 AUC 的对数比(LR)差异。耐受盘试验(TDtest)用于定性检测宿主:结果:与头孢唑烷/他唑巴坦相比,头孢啶醇对九种受试分离物中的六种分离物在 24 小时内的持续存在率较低。在 9 个分离株中,有 8 个在头孢得多合剂组中的 LR 减少率更高,这表明头孢得多合剂组的细菌减少率总体更高、更快。对于头孢羟氨苄,9 个受检分离物中有 5 个在更换为葡萄糖盘后没有再生长,这表明通过 TDtest 没有持久性。对于头孢洛赞/他唑巴坦,有三个分离物没有形成持久菌:结论:与头孢唑烷/他唑巴坦相比,头孢羟氨苄对九种临床铜绿假单胞菌分离物的细菌持久性更低。与头孢妥仑/他唑巴坦相比,Cefiderocol 的嗜肽机制可能通过增强抗芽孢杆菌作用而更具优势。由于顽固菌可导致抗生素耐药性和治疗失败,因此有必要将这些发现与临床相关联。
{"title":"Differential frequency of persister cells in clinically derived isolates of Pseudomonas aeruginosa after exposure to cefiderocol and ceftolozane/tazobactam.","authors":"Aliaa Fouad, Samantha E Nicolau, Pranita D Tamma, Patricia J Simner, David P Nicolau, Christian M Gill","doi":"10.1093/jac/dkae346","DOIUrl":"https://doi.org/10.1093/jac/dkae346","url":null,"abstract":"<p><strong>Background: </strong>Bacterial persistence is a phenomenon whereby a subpopulation of bacteria survive high concentrations of an active antibiotic in the absence of phenotypic alterations. Persisters are associated with chronic and recurrent infections for pathogens including Pseudomonas aeruginosa. Understanding persister profiles of newer antibiotics such as cefiderocol and ceftolozane/tazobactam against P. aeruginosa is warranted as these agents generally target difficult-to-treat infections.</p><p><strong>Methods: </strong>Persister formation was assessed using in vitro assays against nine clinical P. aeruginosa isolates exposed to cefiderocol or ceftolozane/tazobactam. Quantitative persister assays were performed using a stationary phase of bacteria challenged with 10-fold MIC drug concentrations. Persisters were quantitated as the percent persisters at 24 h and the log ratio (LR) difference in AUC for cfu for each antibiotic alone compared with growth control. The tolerance disc test (TDtest) was used to qualitatively detect persisters.</p><p><strong>Results: </strong>Percent persisters at 24 h was lower with cefiderocol compared with ceftolozane/tazobactam for six of the nine tested isolates. Eight of the nine isolates had higher reduction in LR for cefiderocol groups, suggesting an overall higher and more rapid bacterial reduction in cefiderocol groups. For cefiderocol, five of the nine tested isolates lacked regrowth after replacement with glucose disc, suggesting no persistence via the TDtest. For ceftolozane/tazobactam, three isolates lacked persister formation.</p><p><strong>Conclusions: </strong>Cefiderocol resulted in less bacterial persistence relative to ceftolozane/tazobactam against nine clinical P. aeruginosa isolates. Cefiderocol's siderophore mechanism may be advantageous over ceftolozane/tazobactam through enhanced anti-persister effects. Clinical correlation of these findings is warranted as persisters can lead to antibiotic resistance and treatment failure.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500886","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}
引用次数: 0
Online availability of antibiotics from within the UK: shifting patterns from 2016 to 2023. 英国国内抗生素的在线供应:2016 年至 2023 年的变化模式。
IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES Pub Date : 2024-10-22 DOI: 10.1093/jac/dkae341
Sara Elizabeth Boyd, Nina Zhu, Laura Whitney, Rohan Surya, Alison Helen Holmes, Raheelah Ahmad

Background: We previously reported a cross-sectional analysis of online pharmacy practices and processes. Since then, the demand for and context of online healthcare has changed. However, the current state of access to and usage of antibiotics obtained online remains poorly understood.

Objectives: This study aimed to: (i) determine the legality of online pharmacies selling antibiotics in the UK; (ii) describe processes for obtaining antibiotics online; (iii) identify antimicrobial stewardship (AMS) and patient safety issues; and (iv) compare data with those obtained in 2016 to understand changes in context, and set priorities for targeted research in antibiotic access and usage.

Methods: Searches for 'buy antibiotics online' were conducted using 'Google' and 'Yahoo'. The first 10 websites with unique URL addresses for each were reviewed. Analyses were conducted on evidence of pharmacy registration, prescription requirement, whether choice was 'prescriber-driven' or 'consumer-driven', and whether information was required (allergies, comorbidities, pregnancy) or given (adverse effects) prior to purchase.

Results: Twenty unique URL addresses were analysed. Those evidencing UK location (n = 20; 100%) required a prescription and were appropriately registered. For 11 (55%) online pharmacies, decisions were initially consumer-driven for antibiotic choice, but not for dose or duration; contrasting with 2016 when for most (n = 16; 80%), decisions were consumer-driven for antibiotic choice, dose and quantity.

Conclusions: Variation continues to exist in relation to antibiotic practices online. We make several key recommendations for lawmakers and stakeholders. Targeted research, improved public engagement, professional education and new best practice guidelines are urgently needed for online UK antibiotic suppliers.

背景:我们曾对网上药店的实践和流程进行过横向分析。从那时起,在线医疗保健的需求和环境发生了变化。然而,人们对在线抗生素的获取和使用现状仍然知之甚少:本研究旨在(目的:本研究旨在:(i) 确定英国在线药店销售抗生素的合法性;(ii) 描述在线获取抗生素的流程;(iii) 识别抗菌药物管理(AMS)和患者安全问题;(iv) 将数据与 2016 年获得的数据进行比较,以了解背景的变化,并为抗生素获取和使用方面的针对性研究设定优先事项:使用 "谷歌 "和 "雅虎 "搜索 "在线购买抗生素"。对每个网站的前 10 个唯一 URL 地址进行了审查。分析内容包括药房注册证据、处方要求、选择是 "处方驱动 "还是 "消费者驱动",以及购买前是否要求提供信息(过敏、合并症、怀孕)或提供信息(不良反应):分析了 20 个独特的 URL 地址。那些证明位于英国的网址(n = 20;100%)需要处方并进行了适当注册。11家(55%)网上药店的抗生素选择最初是由消费者决定的,但剂量或疗程则不是;这与2016年的情况形成鲜明对比,当时大多数网上药店(n = 16;80%)的抗生素选择、剂量和数量都是由消费者决定的:结论:网上抗生素使用方法仍然存在差异。我们为立法者和利益相关者提出了几项重要建议。英国在线抗生素供应商迫切需要开展有针对性的研究、提高公众参与度、开展专业教育并制定新的最佳实践指南。
{"title":"Online availability of antibiotics from within the UK: shifting patterns from 2016 to 2023.","authors":"Sara Elizabeth Boyd, Nina Zhu, Laura Whitney, Rohan Surya, Alison Helen Holmes, Raheelah Ahmad","doi":"10.1093/jac/dkae341","DOIUrl":"https://doi.org/10.1093/jac/dkae341","url":null,"abstract":"<p><strong>Background: </strong>We previously reported a cross-sectional analysis of online pharmacy practices and processes. Since then, the demand for and context of online healthcare has changed. However, the current state of access to and usage of antibiotics obtained online remains poorly understood.</p><p><strong>Objectives: </strong>This study aimed to: (i) determine the legality of online pharmacies selling antibiotics in the UK; (ii) describe processes for obtaining antibiotics online; (iii) identify antimicrobial stewardship (AMS) and patient safety issues; and (iv) compare data with those obtained in 2016 to understand changes in context, and set priorities for targeted research in antibiotic access and usage.</p><p><strong>Methods: </strong>Searches for 'buy antibiotics online' were conducted using 'Google' and 'Yahoo'. The first 10 websites with unique URL addresses for each were reviewed. Analyses were conducted on evidence of pharmacy registration, prescription requirement, whether choice was 'prescriber-driven' or 'consumer-driven', and whether information was required (allergies, comorbidities, pregnancy) or given (adverse effects) prior to purchase.</p><p><strong>Results: </strong>Twenty unique URL addresses were analysed. Those evidencing UK location (n = 20; 100%) required a prescription and were appropriately registered. For 11 (55%) online pharmacies, decisions were initially consumer-driven for antibiotic choice, but not for dose or duration; contrasting with 2016 when for most (n = 16; 80%), decisions were consumer-driven for antibiotic choice, dose and quantity.</p><p><strong>Conclusions: </strong>Variation continues to exist in relation to antibiotic practices online. We make several key recommendations for lawmakers and stakeholders. Targeted research, improved public engagement, professional education and new best practice guidelines are urgently needed for online UK antibiotic suppliers.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500892","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}
引用次数: 0
Therapeutic drug monitoring (TDM) of β-lactam/β-lactamase inhibitor (BL/BLI) drug combinations: insights from a pharmacometric simulation study. β-内酰胺/β-内酰胺酶抑制剂(BL/BLI)药物组合的治疗药物监测(TDM):药效学模拟研究的启示。
IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES Pub Date : 2024-10-22 DOI: 10.1093/jac/dkae375
Amaury O'Jeanson, Elisabet I Nielsen, Lena E Friberg

Background: The emergence of β-lactamase-producing bacteria has led to the use of β-lactam (BL) antibiotic and β-lactamase inhibitor (BLI) drug combinations. Despite therapeutic drug monitoring (TDM) being endorsed for BLs, the impact of TDM on BLIs remains unclear.

Objectives: Evaluate whether BLIs are available in effective exposures at the site of infection and assess if TDM of BLIs could be of interest.

Methods: Population pharmacokinetic models for 9 BL and BLI compounds were used to simulate drug concentrations at infection sites following EMA-approved dose regimens, considering plasma protein binding and tissue penetration. Predicted target site concentrations were used for probability of target attainment (PTA) analysis.

Results: Using EUCAST targets, satisfactory (≥90%) PTA was observed for BLs in patients with typical renal clearance (CrCL of 80 mL/min) across various sites of infection. However, results varied for BLIs. Avibactam achieved satisfactory PTA only in plasma, with reduced PTAs in abdomen (78%), lung (73%) and prostate (23%). Similarly, tazobactam resulted in unsatisfactory PTAs in intra-abdominal infections (79%), urinary tract infections (64%) and prostatitis (34%). Imipenem-relebactam and meropenem-vaborbactam achieved overall satisfactory PTAs, except in prostatitis and high-MIC infections for the latter combination.

Conclusions: This study highlights the risk of solely relying on TDM of BLs, as this can indicate acceptable exposures of the BL while the BLI concentration, and consequently the combination, can result in suboptimal performance in terms of bacterial killing. Thus, dose adjustments also based on plasma concentration measurements of BLIs, in particular for avibactam and tazobactam, can be valuable in clinical practice to obtain effective exposures at the target site.

背景:产β-内酰胺酶细菌的出现导致了β-内酰胺(BL)抗生素和β-内酰胺酶抑制剂(BLI)药物组合的使用。尽管治疗药物监测(TDM)已被认可用于β-内酰胺类抗生素,但治疗药物监测对β-内酰胺类药物的影响仍不明确:评估在感染部位是否能获得有效暴露的 BLIs,并评估 BLIs 的 TDM 是否有意义:方法:使用9种BL和BLI化合物的群体药代动力学模型模拟在EMA批准的剂量方案下感染部位的药物浓度,同时考虑血浆蛋白结合和组织渗透。预测的靶点浓度用于达标概率(PTA)分析:结果:使用 EUCAST 目标,在不同感染部位,对于具有典型肾清除率(CrCL 为 80 mL/min)的患者,BLs 的 PTA 令人满意(≥90%)。然而,BLIs 的结果却各不相同。阿维菌素仅在血浆中达到了令人满意的 PTA 值,而在腹部(78%)、肺部(73%)和前列腺(23%)中的 PTA 值则有所降低。同样,他唑巴坦在腹腔内感染(79%)、尿路感染(64%)和前列腺炎(34%)中的 PTA 值也不尽人意。亚胺培南-雷巴坦和美罗培南-瓦博拉巴坦的 PTA 值总体令人满意,但后一种组合在前列腺炎和高 MIC 感染中除外:本研究强调了仅仅依赖于BL的TDM的风险,因为这可能表明BL的暴露量是可接受的,而BLI的浓度,以及由此产生的组合,可能导致细菌杀灭效果不理想。因此,在临床实践中,根据BLIs(尤其是阿维巴坦和他唑巴坦)的血浆浓度测量结果进行剂量调整,以获得目标部位的有效暴露量,可能会很有价值。
{"title":"Therapeutic drug monitoring (TDM) of β-lactam/β-lactamase inhibitor (BL/BLI) drug combinations: insights from a pharmacometric simulation study.","authors":"Amaury O'Jeanson, Elisabet I Nielsen, Lena E Friberg","doi":"10.1093/jac/dkae375","DOIUrl":"https://doi.org/10.1093/jac/dkae375","url":null,"abstract":"<p><strong>Background: </strong>The emergence of β-lactamase-producing bacteria has led to the use of β-lactam (BL) antibiotic and β-lactamase inhibitor (BLI) drug combinations. Despite therapeutic drug monitoring (TDM) being endorsed for BLs, the impact of TDM on BLIs remains unclear.</p><p><strong>Objectives: </strong>Evaluate whether BLIs are available in effective exposures at the site of infection and assess if TDM of BLIs could be of interest.</p><p><strong>Methods: </strong>Population pharmacokinetic models for 9 BL and BLI compounds were used to simulate drug concentrations at infection sites following EMA-approved dose regimens, considering plasma protein binding and tissue penetration. Predicted target site concentrations were used for probability of target attainment (PTA) analysis.</p><p><strong>Results: </strong>Using EUCAST targets, satisfactory (≥90%) PTA was observed for BLs in patients with typical renal clearance (CrCL of 80 mL/min) across various sites of infection. However, results varied for BLIs. Avibactam achieved satisfactory PTA only in plasma, with reduced PTAs in abdomen (78%), lung (73%) and prostate (23%). Similarly, tazobactam resulted in unsatisfactory PTAs in intra-abdominal infections (79%), urinary tract infections (64%) and prostatitis (34%). Imipenem-relebactam and meropenem-vaborbactam achieved overall satisfactory PTAs, except in prostatitis and high-MIC infections for the latter combination.</p><p><strong>Conclusions: </strong>This study highlights the risk of solely relying on TDM of BLs, as this can indicate acceptable exposures of the BL while the BLI concentration, and consequently the combination, can result in suboptimal performance in terms of bacterial killing. Thus, dose adjustments also based on plasma concentration measurements of BLIs, in particular for avibactam and tazobactam, can be valuable in clinical practice to obtain effective exposures at the target site.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500893","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}
引用次数: 0
Deleterious effects of a combination therapy using fluoroquinolones and tetracyclines for the treatment of Japanese spotted fever: a retrospective cohort study based on a Japanese hospital database-authors' response. 使用氟喹诺酮类药物和四环素类药物联合治疗日本斑疹热的不良反应:基于日本医院数据库的回顾性队列研究--作者的回应。
IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES Pub Date : 2024-10-22 DOI: 10.1093/jac/dkae378
Ikkoh Yasuda, Michiko Toizumi, Eiichiro Sando
{"title":"Deleterious effects of a combination therapy using fluoroquinolones and tetracyclines for the treatment of Japanese spotted fever: a retrospective cohort study based on a Japanese hospital database-authors' response.","authors":"Ikkoh Yasuda, Michiko Toizumi, Eiichiro Sando","doi":"10.1093/jac/dkae378","DOIUrl":"10.1093/jac/dkae378","url":null,"abstract":"","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500877","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}
引用次数: 0
Inoculum effect of cefiderocol against NDM-1 producing Escherichia coli in vitro and in a murine model of peritonitis. 头孢克洛在体外和鼠腹膜炎模型中对产生 NDM-1 的大肠埃希菌的接种效果。
IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES Pub Date : 2024-10-22 DOI: 10.1093/jac/dkae368
Anne-Sophie Godron, Ariane Amoura, Claire Pistien, André Birgy, Sophie Magreault, Agnès B Jousset, Vincent Jullien, Agnès Lefort, Bruno Fantin, Imane El Meouche, Victoire de Lastours

Introduction: Cefiderocol is a siderophore cephalosporin active in vitro against carbapenemase-producing Enterobacterales, including New Delhi metallo-β-lactamases (NDM-1). A significant impact of the size of bacterial inoculum on its efficacy has been described in vitro, the clinical impact of which is unclear. Here, we analyse the inoculum effect of cefiderocol against E. coli-NDM-1 in vitro and in a murine peritonitis model.

Materials and methods: Escherichia coli 62-pTOPO and its isogenic variant expressing NDM-1, 62-pTOPO-NDM, were constructed from a clinical strain. MICs and bactericidal kinetics were determined at standard (105 cfu/mL) and high inoculum (107 cfu/mL). The in vivo effect was assessed in a severe murine peritonitis model, comparing low (106 cfu/mL) and high (108 cfu/mL) inoculum. Survival rates, organ sterilization and bacterial counts in spleen and peritoneal fluid were compared.

Results: Cefiderocol MICs for 62-pTOPO and 62-pTOPO-NDM at standard and high inoculum were 0.008, 2, 2 and 1024 mg/L, respectively. Bactericidal activity was not achieved in vitro for 62-pTOPO-NDM at high inoculum with high cefiderocol concentrations (16 mg/L). In vivo, for 62-pTOPO-NDM, no difference was found in survival, organ sterilization or bacterial counts between low and high inoculum. For 62-pTOPO, no difference was observed in survival, despite less organ sterilization and higher bacterial counts in organs with the high inoculum.

Conclusion: A significant inoculum effect of cefiderocol was observed in vitro for 62-pTOPO and 62-pTOPO-NDM. However, the effectiveness of cefiderocol was not reduced in vivo with a high bacterial inoculum. In vitro inoculum effect of cefiderocol may not be clinically significant.

简介头孢羟氨苄(Cefiderocol)是一种嗜苷头孢菌素,在体外对产碳青霉烯酶肠杆菌(包括新德里金属-β-内酰胺酶(NDM-1))有活性。体外研究表明,细菌接种量的大小对其药效有很大影响,但其临床影响尚不清楚。在此,我们分析了头孢克洛在体外和小鼠腹膜炎模型中对大肠杆菌-NDM-1的接种效果:大肠杆菌 62-pTOPO 及其表达 NDM-1 的同源变体 62-pTOPO-NDM,均由临床菌株构建而成。测定了标准(105 cfu/mL)和高接种量(107 cfu/mL)下的 MIC 和杀菌动力学。在严重的小鼠腹膜炎模型中,对低接种量(106 cfu/mL)和高接种量(108 cfu/mL)的体内效果进行了评估。比较了存活率、器官消毒以及脾脏和腹腔液中的细菌计数:结果:在标准和高接种量下,62-pTOPO 和 62-pTOPO-NDM 的头孢菌素 MIC 分别为 0.008、2、2 和 1024 mg/L。在体外,62-pTOPO-NDM 在高接种量和高浓度 cefiderocol(16 毫克/升)条件下未达到杀菌活性。在体内,62-pTOPO-NDM 的存活率、器官消毒或细菌计数在低接种量和高接种量之间没有差异。对于 62-pTOPO,尽管高接种量的器官灭菌率较低,细菌计数较高,但存活率没有差异:结论:对于 62-pTOPO 和 62-pTOPO-NDM,在体外观察到头孢羟氨苄具有明显的接种量效应。然而,在体内高细菌接种量下,头孢羟氨苄的效果并没有降低。头孢羟氨苄的体外接种量效应可能没有临床意义。
{"title":"Inoculum effect of cefiderocol against NDM-1 producing Escherichia coli in vitro and in a murine model of peritonitis.","authors":"Anne-Sophie Godron, Ariane Amoura, Claire Pistien, André Birgy, Sophie Magreault, Agnès B Jousset, Vincent Jullien, Agnès Lefort, Bruno Fantin, Imane El Meouche, Victoire de Lastours","doi":"10.1093/jac/dkae368","DOIUrl":"https://doi.org/10.1093/jac/dkae368","url":null,"abstract":"<p><strong>Introduction: </strong>Cefiderocol is a siderophore cephalosporin active in vitro against carbapenemase-producing Enterobacterales, including New Delhi metallo-β-lactamases (NDM-1). A significant impact of the size of bacterial inoculum on its efficacy has been described in vitro, the clinical impact of which is unclear. Here, we analyse the inoculum effect of cefiderocol against E. coli-NDM-1 in vitro and in a murine peritonitis model.</p><p><strong>Materials and methods: </strong>Escherichia coli 62-pTOPO and its isogenic variant expressing NDM-1, 62-pTOPO-NDM, were constructed from a clinical strain. MICs and bactericidal kinetics were determined at standard (105 cfu/mL) and high inoculum (107 cfu/mL). The in vivo effect was assessed in a severe murine peritonitis model, comparing low (106 cfu/mL) and high (108 cfu/mL) inoculum. Survival rates, organ sterilization and bacterial counts in spleen and peritoneal fluid were compared.</p><p><strong>Results: </strong>Cefiderocol MICs for 62-pTOPO and 62-pTOPO-NDM at standard and high inoculum were 0.008, 2, 2 and 1024 mg/L, respectively. Bactericidal activity was not achieved in vitro for 62-pTOPO-NDM at high inoculum with high cefiderocol concentrations (16 mg/L). In vivo, for 62-pTOPO-NDM, no difference was found in survival, organ sterilization or bacterial counts between low and high inoculum. For 62-pTOPO, no difference was observed in survival, despite less organ sterilization and higher bacterial counts in organs with the high inoculum.</p><p><strong>Conclusion: </strong>A significant inoculum effect of cefiderocol was observed in vitro for 62-pTOPO and 62-pTOPO-NDM. However, the effectiveness of cefiderocol was not reduced in vivo with a high bacterial inoculum. In vitro inoculum effect of cefiderocol may not be clinically significant.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500889","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}
引用次数: 0
Emergent resistance-associated mutations at first- or second-line HIV-1 virologic failure with second-generation InSTIs in two- and three-drug regimens: the Virostar-1 study. 在两药和三药治疗方案中使用第二代 InSTIs 导致一线或二线 HIV-1 病毒学治疗失败时出现的耐药性相关突变:Virostar-1 研究。
IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES Pub Date : 2024-10-22 DOI: 10.1093/jac/dkae377
Anne-Geneviève Marcelin, Cathia Soulie, Marc Wirden, Guillaume Barriere, François Durand, Charlotte Charpentier, Diane Descamps, Vincent Calvez

Background: Second-generation integrase strand transfer inhibitors (InSTIs) have a high barrier to resistance and potent antiretroviral activity. They are recommended as first- or second-line (FL and SL) options in two- and three-drug regimens (2DR and 3DR) in international treatment guidelines. However, there are limited real-world data on emerging resistance at the time of virological failure (VF) with these regimens.

Objectives: The Virostar-1 study objective is to analyse the emergence of resistance-associated mutations (RAMs) over 3 years with DTG-based 2DRs and DTG- or bictegravir (BIC)-based 3DRs in people living with HIV (PLWH) experiencing a VF (FL or SL).

Methods: Retrospective analysis of genotypic resistance detected at the time of a FL or SL VF with BIC/FTC/TAF, DTG/ABC/3TC, DTG/3TC and DTG/RPV between 2019 and 2022 was conducted from a French multicentre database. VF was defined as two consecutive HIV-1 plasma viral loads > 50 c/mL. Sanger assays were performed at VF within standard clinical care. Resistance mutations were reported using the ANRS algorithm. Selection biases prevent group comparisons.

Results: During the period, N = 5986 PLWH were followed either in FL or SL. The VF rate was overall low: BIC/FTC/TAF, 6.8%; DTG/ABC/3TC, 7.5%; DTG/3TC, 5.1%; and DTG/RPV, 2.1%. Some emergent InSTI or NRTI RAMs were detected with BIC/FTC/TAF 4%, DTG/ABC/3TC 8.5%, DTG/3TC 18% and 39% emergent NNRTI RAMs with DTG/RPV. However, a complete absence of dual resistance against NRTIs and InSTIs was observed.

Conclusions: We detected rare emergent InSTI RAMs and few emergent NRTI RAMs in PLWH failing DTG- or BIC-based regimens in FL or SL. The observed rates of emergent RAMs at VF were 4% with BIC/FTC/TAF, 8.5% with DTG/ABC/3TC, 18% with DTG/3TC and 39% with DTG/RPV.

背景:第二代整合酶链转移抑制剂(InSTIs)具有较高的耐药屏障和强大的抗逆转录病毒活性。国际治疗指南推荐在两药和三药治疗方案(2DR 和 3DR)中将其作为一线或二线(FL 和 SL)选择。然而,在使用这些方案出现病毒学失败(VF)时,有关新出现耐药性的实际数据却很有限:Virostar-1研究的目的是分析以DTG为基础的2DR和以DTG或比特拉韦(BIC)为基础的3DR在经历VF(FL或SL)的艾滋病病毒感染者(PLWH)中的3年耐药性相关突变(RAM)的出现情况:法国多中心数据库对2019年至2022年期间使用BIC/FTC/TAF、DTG/ABC/3TC、DTG/3TC和DTG/RPV治疗FL或SL VF时检测到的基因型耐药性进行了回顾性分析。VF定义为连续两次HIV-1血浆病毒载量>50 c/mL。在标准临床治疗范围内的 VF 期进行 Sanger 分析。耐药性突变采用 ANRS 算法进行报告。由于存在选择偏差,因此无法进行分组比较:在此期间,共有 5986 名 PLWH 接受了 FL 或 SL 的随访。VF率总体较低:BIC/FTC/TAF,6.8%;DTG/ABC/3TC,7.5%;DTG/3TC,5.1%;DTG/RPV,2.1%。在 BIC/FTC/TAF 4%、DTG/ABC/3TC 8.5%、DTG/3TC 18%、DTG/RPV 39% 和 NNRTI RAM 中发现了一些新出现的 InSTI 或 NRTI RAM。然而,我们观察到完全不存在对 NRTIs 和 InSTIs 的双重耐药性:我们在 FL 或 SL 地区使用 DTG 或 BIC 方案失败的 PLWH 中发现了罕见的 InSTI RAMs 和少数 NRTI RAMs。在 VF 期观察到的突发 RAM 发生率为:BIC/FTC/TAF 4%,DTG/ABC/3TC 8.5%,DTG/3TC 18%,DTG/RPV 39%。
{"title":"Emergent resistance-associated mutations at first- or second-line HIV-1 virologic failure with second-generation InSTIs in two- and three-drug regimens: the Virostar-1 study.","authors":"Anne-Geneviève Marcelin, Cathia Soulie, Marc Wirden, Guillaume Barriere, François Durand, Charlotte Charpentier, Diane Descamps, Vincent Calvez","doi":"10.1093/jac/dkae377","DOIUrl":"https://doi.org/10.1093/jac/dkae377","url":null,"abstract":"<p><strong>Background: </strong>Second-generation integrase strand transfer inhibitors (InSTIs) have a high barrier to resistance and potent antiretroviral activity. They are recommended as first- or second-line (FL and SL) options in two- and three-drug regimens (2DR and 3DR) in international treatment guidelines. However, there are limited real-world data on emerging resistance at the time of virological failure (VF) with these regimens.</p><p><strong>Objectives: </strong>The Virostar-1 study objective is to analyse the emergence of resistance-associated mutations (RAMs) over 3 years with DTG-based 2DRs and DTG- or bictegravir (BIC)-based 3DRs in people living with HIV (PLWH) experiencing a VF (FL or SL).</p><p><strong>Methods: </strong>Retrospective analysis of genotypic resistance detected at the time of a FL or SL VF with BIC/FTC/TAF, DTG/ABC/3TC, DTG/3TC and DTG/RPV between 2019 and 2022 was conducted from a French multicentre database. VF was defined as two consecutive HIV-1 plasma viral loads > 50 c/mL. Sanger assays were performed at VF within standard clinical care. Resistance mutations were reported using the ANRS algorithm. Selection biases prevent group comparisons.</p><p><strong>Results: </strong>During the period, N = 5986 PLWH were followed either in FL or SL. The VF rate was overall low: BIC/FTC/TAF, 6.8%; DTG/ABC/3TC, 7.5%; DTG/3TC, 5.1%; and DTG/RPV, 2.1%. Some emergent InSTI or NRTI RAMs were detected with BIC/FTC/TAF 4%, DTG/ABC/3TC 8.5%, DTG/3TC 18% and 39% emergent NNRTI RAMs with DTG/RPV. However, a complete absence of dual resistance against NRTIs and InSTIs was observed.</p><p><strong>Conclusions: </strong>We detected rare emergent InSTI RAMs and few emergent NRTI RAMs in PLWH failing DTG- or BIC-based regimens in FL or SL. The observed rates of emergent RAMs at VF were 4% with BIC/FTC/TAF, 8.5% with DTG/ABC/3TC, 18% with DTG/3TC and 39% with DTG/RPV.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500887","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}
引用次数: 0
Identifying AWaRe indicators for appropriate antibiotic use: a narrative review. 确定合理使用抗生素的 AWaRe 指标:叙述性综述。
IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES Pub Date : 2024-10-18 DOI: 10.1093/jac/dkae370
Elisa Funiciello, Giulia Lorenzetti, Aislinn Cook, Jan Goelen, Catrin E Moore, Stephen M Campbell, Brian Godman, Deborah Tong, Benedikt Huttner, Pem Chuki, Michael Sharland

Introduction: Quality indicators (QIs) are widely used tools for antibiotic stewardship programmes. The Access, Watch, Reserve (AWaRe) system has been developed by the WHO to classify antibiotics based on their spectrum of activity and potential selection of antibiotic resistance. This review aimed to identify existing indicators for optimal antibiotic use to inform the development of future AWaRe QIs.

Methods: A literature search was performed in PubMed. We included articles describing QIs for hospital and primary healthcare antibiotic use. We extracted information about (i) the type of infection; (ii) setting; (iii) target for quality assessment; and (iv) methodology used for the development. We then identified the indicators that reflected the guidance provided in the AWaRe system.

Results: A total of 773 indicators for antibiotic use were identified. The management of health services and/or workers, the consumption of antibiotics, and antibiotic prescribing/dispensing were the principal targets for quality assessment. There was a similar distribution of indicators across primary and secondary care. For infection-specific indicators, about 50% focused on respiratory tract infections. Only a few QIs included information on review treatment or microbiological investigations. Although only 8 (1%) indicators directly cited the AWaRe system in the wording of the indicators, 445 (57.6%) indicators reflected the guidance provided in the AWaRe book.

Conclusions: A high number of indicators for appropriate antibiotic use have been developed. However, few are currently based directly on the WHO AWaRe system. There is a clear need to develop globally applicable AWaRe based indicators that can be integrated into antibiotic stewardship programmes.

导言:质量指标(QIs)是抗生素管理计划中广泛使用的工具。世界卫生组织开发了 "获取、观察、储备"(AWaRe)系统,根据抗生素的活性范围和抗生素耐药性的潜在选择对抗生素进行分类。本综述旨在确定最佳抗生素使用的现有指标,为未来 AWaRe QIs 的开发提供参考:方法:在 PubMed 上进行文献检索。我们收录了描述医院和基层医疗机构抗生素使用 QIs 的文章。我们提取了以下信息:(i) 感染类型;(ii) 环境;(iii) 质量评估目标;(iv) 制定方法。然后,我们确定了反映 AWaRe 系统所提供指导的指标:结果:共确定了 773 项抗生素使用指标。医疗服务和/或工作人员的管理、抗生素的使用以及抗生素的处方/配药是质量评估的主要目标。指标在初级和二级医疗机构的分布情况相似。在感染特异性指标方面,约 50%侧重于呼吸道感染。只有少数质量指标包括复查治疗或微生物学检查的信息。虽然只有 8 项(1%)指标在指标措辞中直接引用了 AWaRe 系统,但有 445 项(57.6%)指标反映了 AWaRe 书籍中提供的指导:结论:已经制定了大量抗生素合理使用指标。然而,目前直接基于世界卫生组织 AWaRe 系统的指标很少。显然有必要制定全球适用的基于 AWaRe 的指标,并将其纳入抗生素监管计划。
{"title":"Identifying AWaRe indicators for appropriate antibiotic use: a narrative review.","authors":"Elisa Funiciello, Giulia Lorenzetti, Aislinn Cook, Jan Goelen, Catrin E Moore, Stephen M Campbell, Brian Godman, Deborah Tong, Benedikt Huttner, Pem Chuki, Michael Sharland","doi":"10.1093/jac/dkae370","DOIUrl":"https://doi.org/10.1093/jac/dkae370","url":null,"abstract":"<p><strong>Introduction: </strong>Quality indicators (QIs) are widely used tools for antibiotic stewardship programmes. The Access, Watch, Reserve (AWaRe) system has been developed by the WHO to classify antibiotics based on their spectrum of activity and potential selection of antibiotic resistance. This review aimed to identify existing indicators for optimal antibiotic use to inform the development of future AWaRe QIs.</p><p><strong>Methods: </strong>A literature search was performed in PubMed. We included articles describing QIs for hospital and primary healthcare antibiotic use. We extracted information about (i) the type of infection; (ii) setting; (iii) target for quality assessment; and (iv) methodology used for the development. We then identified the indicators that reflected the guidance provided in the AWaRe system.</p><p><strong>Results: </strong>A total of 773 indicators for antibiotic use were identified. The management of health services and/or workers, the consumption of antibiotics, and antibiotic prescribing/dispensing were the principal targets for quality assessment. There was a similar distribution of indicators across primary and secondary care. For infection-specific indicators, about 50% focused on respiratory tract infections. Only a few QIs included information on review treatment or microbiological investigations. Although only 8 (1%) indicators directly cited the AWaRe system in the wording of the indicators, 445 (57.6%) indicators reflected the guidance provided in the AWaRe book.</p><p><strong>Conclusions: </strong>A high number of indicators for appropriate antibiotic use have been developed. However, few are currently based directly on the WHO AWaRe system. There is a clear need to develop globally applicable AWaRe based indicators that can be integrated into antibiotic stewardship programmes.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466016","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}
引用次数: 0
Quantitative performance of humanized serum and epithelial lining fluid exposures of tigecycline and levofloxacin against a challenge set of Klebsiella pneumoniae and Pseudomonas aeruginosa in a standardized neutropenic murine pneumonia model. 在标准化中性鼠肺炎模型中,人源化血清和上皮内衬液暴露替加环素和左氧氟沙星对一组肺炎克雷伯菌和铜绿假单胞菌挑战的定量表现。
IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES Pub Date : 2024-10-18 DOI: 10.1093/jac/dkae333
Andrew J Fratoni, Alissa M Padgett, Erin M Duffy, David P Nicolau

Background: Lack of uniformity in infection models complicates preclinical development. The COMBINE protocol has standardized the murine neutropenic pneumonia model. Herein we provide benchmark efficacy data of humanized exposures of tigecycline and levofloxacin in plasma and epithelial lining fluid (ELF) against a collection of Klebsiella pneumoniae and Pseudomonas aeruginosa.

Methods: Following the COMBINE protocol, plasma and ELF human-simulated regimens (HSRs) of tigecycline 100 mg followed by 50 mg q12h and levofloxacin 750 mg once daily were developed and confirmed in the murine neutropenic pneumonia model. Tigecycline HSRs were tested against seven K. pneumoniae isolates. Levofloxacin HSRs were assessed against 10 K. pneumoniae and 9 P. aeruginosa. The change in cfu/lung over 24 h for each treatment was calculated. Each isolate was tested in duplicate against both the plasma and ELF HSRs on separate experiment days.

Results: Tigecycline 1.8 and 3 mg/kg q12h achieved humanized exposures of serum and ELF, respectively. Levofloxacin 120 and 90 mg/kg q8h led to fAUC exposures in plasma and ELF similar to in humans. Both tigecycline regimens were ineffective across the MIC range. Levofloxacin regimens achieved multilog kill against susceptible isolates, and no appreciable cfu/lung reductions in isolates with an MIC of ≥32 mg/L. Differences in cfu/lung were evident between the levofloxacin plasma and ELF HSRs against isolates with MICs of 4 and 8 mg/L.

Conclusions: Administering HSRs of tigecycline and levofloxacin based on both serum/plasma and ELF in the COMBINE pneumonia model resulted in cfu/lung values reasonably aligned with MIC. These data serve as translational benchmarks for future investigations with novel compounds.

背景:感染模型缺乏统一性使临床前开发变得复杂。COMBINE 方案规范了小鼠中性肺炎模型。在此,我们提供了血浆和上皮内衬液(ELF)中替加环素和左氧氟沙星人源化暴露对肺炎克雷伯菌和铜绿假单胞菌的基准疗效数据:按照 COMBINE 方案,开发了替加环素 100 毫克、50 毫克 q12h 和左氧氟沙星 750 毫克每日一次的血浆和上皮内衬液人体模拟方案(HSR),并在小鼠中性粒细胞减少性肺炎模型中进行了确认。针对七种肺炎克氏菌分离物测试了替加环素 HSR。左氧氟沙星 HSR 针对 10 个肺炎克氏菌和 9 个铜绿假单胞菌进行了评估。计算每种处理 24 小时内 cfu/肺的变化。在不同的实验日,针对血浆和 ELF HSR 对每种分离物进行重复测试:结果:替加环素 1.8 和 3 mg/kg q12h 分别达到了血清和 ELF 的人源化暴露。左氧氟沙星120毫克和90毫克/千克 q8小时后,血浆和ELF中的fAUC暴露量与人体相似。两种替加环素治疗方案在MIC范围内均无效。左氧氟沙星治疗方案对易感分离株有多倍杀灭作用,对MIC≥32 mg/L的分离株的cfu/lung没有明显降低。左氧氟沙星血浆 HSR 和 ELF HSR 对 MIC 值为 4 毫克/升和 8 毫克/升的分离株的 cfu/lung 降幅差异明显:结论:在 COMBINE 肺炎模型中使用基于血清/血浆和 ELF 的替加环素和左氧氟沙星 HSR,其 cfu/lung 值与 MIC 值相当一致。这些数据可作为今后研究新型化合物的转化基准。
{"title":"Quantitative performance of humanized serum and epithelial lining fluid exposures of tigecycline and levofloxacin against a challenge set of Klebsiella pneumoniae and Pseudomonas aeruginosa in a standardized neutropenic murine pneumonia model.","authors":"Andrew J Fratoni, Alissa M Padgett, Erin M Duffy, David P Nicolau","doi":"10.1093/jac/dkae333","DOIUrl":"https://doi.org/10.1093/jac/dkae333","url":null,"abstract":"<p><strong>Background: </strong>Lack of uniformity in infection models complicates preclinical development. The COMBINE protocol has standardized the murine neutropenic pneumonia model. Herein we provide benchmark efficacy data of humanized exposures of tigecycline and levofloxacin in plasma and epithelial lining fluid (ELF) against a collection of Klebsiella pneumoniae and Pseudomonas aeruginosa.</p><p><strong>Methods: </strong>Following the COMBINE protocol, plasma and ELF human-simulated regimens (HSRs) of tigecycline 100 mg followed by 50 mg q12h and levofloxacin 750 mg once daily were developed and confirmed in the murine neutropenic pneumonia model. Tigecycline HSRs were tested against seven K. pneumoniae isolates. Levofloxacin HSRs were assessed against 10 K. pneumoniae and 9 P. aeruginosa. The change in cfu/lung over 24 h for each treatment was calculated. Each isolate was tested in duplicate against both the plasma and ELF HSRs on separate experiment days.</p><p><strong>Results: </strong>Tigecycline 1.8 and 3 mg/kg q12h achieved humanized exposures of serum and ELF, respectively. Levofloxacin 120 and 90 mg/kg q8h led to fAUC exposures in plasma and ELF similar to in humans. Both tigecycline regimens were ineffective across the MIC range. Levofloxacin regimens achieved multilog kill against susceptible isolates, and no appreciable cfu/lung reductions in isolates with an MIC of ≥32 mg/L. Differences in cfu/lung were evident between the levofloxacin plasma and ELF HSRs against isolates with MICs of 4 and 8 mg/L.</p><p><strong>Conclusions: </strong>Administering HSRs of tigecycline and levofloxacin based on both serum/plasma and ELF in the COMBINE pneumonia model resulted in cfu/lung values reasonably aligned with MIC. These data serve as translational benchmarks for future investigations with novel compounds.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466019","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}
引用次数: 0
Ceftriaxone-resistant Neisseria gonorrhoeae detected in England, 2015-24: an observational analysis. 2015-24 年英格兰发现的耐头孢曲松淋病奈瑟菌:观察分析。
IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES Pub Date : 2024-10-17 DOI: 10.1093/jac/dkae369
Helen Fifer, Michel Doumith, Luciana Rubinstein, Laura Mitchell, Mark Wallis, Selena Singh, Gurmit Jagjit Singh, Michael Rayment, John Evans-Jones, Alison Blume, Olamide Dosekun, Kenny Poon, Achyuta Nori, Michaela Day, Rachel Pitt-Kendall, Suzy Sun, Prarthana Narayanan, Emma Callan, Anna Vickers, Jack Minshull, Kirsty F Bennet, James E C Johnson, John Saunders, Sarah Alexander, Hamish Mohammed, Neil Woodford, Katy Sinka, Michelle Cole

Objectives: Since June 2022, there has been a rise in the number of ceftriaxone-resistant Neisseria gonorrhoeae cases detected in England (n = 15), of which a third were XDR. We describe the demographic and clinical details of the recent cases and investigate the phenotypic and molecular characteristics of the isolates. For a comprehensive overview, we also reviewed 16 ceftriaxone-resistant cases previously identified in England since December 2015 and performed a global genomic comparison of all publicly available ceftriaxone-resistant N. gonorrhoeae strains with mosaic penA alleles.

Methods: All N. gonorrhoeae isolates resistant to ceftriaxone (MIC > 0.125 mg/L) were whole-genome sequenced and compared with 142 global sequences of ceftriaxone-resistant N. gonorrhoeae. Demographic, behavioural and clinical data were collected.

Results: All cases were heterosexual, and most infections were associated with travel from the Asia-Pacific region. However, some had not travelled outside England within the previous few months. There were no ceftriaxone genital treatment failures, but three of five pharyngeal infections and the only rectal infection failed treatment. The isolates represented 13 different MLST STs, and most had the mosaic penA-60.001 allele. The global genomes clustered into eight major phylogroups, with regional associations. All XDR isolates belonged to the same phylogroup, represented by MLST ST16406.

Conclusions: Most cases of ceftriaxone-resistant N. gonorrhoeae detected in England were associated with travel from the Asia-Pacific region. All genital infections were successfully treated with ceftriaxone, but there were extragenital treatment failures. Ceftriaxone resistance continues to be associated with the penA-60.001 allele within multiple genetic backgrounds and with widespread dissemination in the Asia-Pacific region.

目标:自 2022 年 6 月以来,英格兰发现的耐头孢曲松淋病奈瑟菌病例数量有所增加(n = 15),其中三分之一为 XDR。我们描述了近期病例的人口统计学和临床细节,并调查了分离物的表型和分子特征。为了全面了解情况,我们还回顾了自2015年12月以来在英格兰发现的16例耐药头孢曲松病例,并对所有公开发表的耐头孢曲松淋球菌菌株进行了全球基因组比较,这些菌株均具有嵌合penA等位基因:对所有对头孢曲松耐药(MIC > 0.125 mg/L)的淋球菌分离株进行全基因组测序,并与全球142株头孢曲松耐药淋球菌序列进行比较。收集了人口统计学、行为学和临床数据:结果:所有病例均为异性恋者,大多数感染与来自亚太地区的旅行有关。不过,有些病例在过去几个月中没有出过英国。没有头孢曲松生殖器治疗失败的病例,但五例咽部感染中的三例和唯一的直肠感染治疗失败。这些分离株代表了 13 种不同的 MLST ST,其中大多数具有镶嵌的 penA-60.001 等位基因。全球基因组分为八大系统群,并具有区域关联性。所有 XDR 分离物都属于同一系统群,以 MLST ST16406 为代表:英国发现的大多数耐头孢曲松淋球菌病例都与来自亚太地区的旅行有关。所有生殖器感染病例都成功接受了头孢曲松治疗,但也有生殖器外治疗失败的病例。头孢曲松耐药性仍然与多种遗传背景中的penA-60.001等位基因有关,并在亚太地区广泛传播。
{"title":"Ceftriaxone-resistant Neisseria gonorrhoeae detected in England, 2015-24: an observational analysis.","authors":"Helen Fifer, Michel Doumith, Luciana Rubinstein, Laura Mitchell, Mark Wallis, Selena Singh, Gurmit Jagjit Singh, Michael Rayment, John Evans-Jones, Alison Blume, Olamide Dosekun, Kenny Poon, Achyuta Nori, Michaela Day, Rachel Pitt-Kendall, Suzy Sun, Prarthana Narayanan, Emma Callan, Anna Vickers, Jack Minshull, Kirsty F Bennet, James E C Johnson, John Saunders, Sarah Alexander, Hamish Mohammed, Neil Woodford, Katy Sinka, Michelle Cole","doi":"10.1093/jac/dkae369","DOIUrl":"https://doi.org/10.1093/jac/dkae369","url":null,"abstract":"<p><strong>Objectives: </strong>Since June 2022, there has been a rise in the number of ceftriaxone-resistant Neisseria gonorrhoeae cases detected in England (n = 15), of which a third were XDR. We describe the demographic and clinical details of the recent cases and investigate the phenotypic and molecular characteristics of the isolates. For a comprehensive overview, we also reviewed 16 ceftriaxone-resistant cases previously identified in England since December 2015 and performed a global genomic comparison of all publicly available ceftriaxone-resistant N. gonorrhoeae strains with mosaic penA alleles.</p><p><strong>Methods: </strong>All N. gonorrhoeae isolates resistant to ceftriaxone (MIC > 0.125 mg/L) were whole-genome sequenced and compared with 142 global sequences of ceftriaxone-resistant N. gonorrhoeae. Demographic, behavioural and clinical data were collected.</p><p><strong>Results: </strong>All cases were heterosexual, and most infections were associated with travel from the Asia-Pacific region. However, some had not travelled outside England within the previous few months. There were no ceftriaxone genital treatment failures, but three of five pharyngeal infections and the only rectal infection failed treatment. The isolates represented 13 different MLST STs, and most had the mosaic penA-60.001 allele. The global genomes clustered into eight major phylogroups, with regional associations. All XDR isolates belonged to the same phylogroup, represented by MLST ST16406.</p><p><strong>Conclusions: </strong>Most cases of ceftriaxone-resistant N. gonorrhoeae detected in England were associated with travel from the Asia-Pacific region. All genital infections were successfully treated with ceftriaxone, but there were extragenital treatment failures. Ceftriaxone resistance continues to be associated with the penA-60.001 allele within multiple genetic backgrounds and with widespread dissemination in the Asia-Pacific region.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466114","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}
引用次数: 0
Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA. 米诺环素联合利福平在 MRSA 引起的复杂皮肤和皮肤结构感染患者中的群体药代动力学/药效学。
IF 3.9 2区 医学 Q1 INFECTIOUS DISEASES Pub Date : 2024-10-16 DOI: 10.1093/jac/dkae363
Sonia Luque Pardos, William Hope, Antigone Kotsaki, Shampa Das, Evangelos J Giamarellos-Bourboulis, Theano Kontopoulouk, Karolina Akinosoglou, Miriam O'Hare, Marie L G Attwood, Karen E Bowker, Alan R Noel, Andrew M Lovering, Mark A J Bayliss, Rebecca N Evans, Alasdair P MacGowan

Background: The population pharmacokinetics/pharmacodynamics (PK/PD) of minocycline, rifampicin and linezolid in patients with complicated skin and soft tissue infections (cSSTIs) caused by MRSA are described.

Methods: Samples were collected in a Phase 4 study of oral minocycline plus rifampicin versus linezolid showing minocycline plus rifampicin to be non-inferior to linezolid. Antibiotics were assayed by HPLC or LC-MS, and a population PK model was developed using Pmetrics. The association between PK/PD indices and patient outcomes was explored.

Results: A three-compartment model (with an absorption compartment) with first-order input and elimination best described the data for the three drugs. No covariates were included in the final model. The population median values (95% credibility limits) of the clearance and volume of distribution were 7.412 L/h (5.121-8.361) and 14.155 L (6.799-33.901) for minocycline, 5.683 L/h (3.703-7.726) and 7.736 L (6.031-8.948) for rifampicin, and 1.970 L/h (1.326-2.499) and 20.169 L (12.857-32.629) for linezolid, respectively. Maximum a posteriori probability-Bayesian estimation plots of observed versus predicted had a slope of 0.999 r20.967 for minocycline, slope 0.998 r20.769 for rifampicin and slope 0.998 r20.895 for linezolid. PK/PD indices were not related to clinical outcome. Taking a translational minocycline fAUC24h/MIC target of >0.5 for minocycline in the presence of rifampicin, 96% (49/51) of patients reached the target.

Conclusions: Population PK models of minocycline, rifampicin and linezolid were developed in patients with MRSA cSSTI and almost all patients reached the predefined PD index targets. As a result, neither AUC, MIC nor the AUC/MIC ratio could be related to clinical outcome.

背景:描述了米诺环素、利福平和利奈唑胺在MRSA引起的复杂皮肤和软组织感染(cSSTI)患者中的群体药代动力学/药效学(PK/PD):在口服米诺环素加利福平与利奈唑胺的第 4 期研究中收集了样本,结果显示米诺环素加利福平与利奈唑胺的疗效相当。抗生素通过 HPLC 或 LC-MS 进行检测,并使用 Pmetrics 建立了群体 PK 模型。探讨了 PK/PD 指数与患者预后之间的关联:结果:采用一阶输入和消除的三室模型(含一个吸收室)对三种药物的数据进行了最佳描述。最终模型中未包含协变量。米诺环素的清除率和分布容积的人群中位值(95% 可信限)分别为 7.412 L/h (5.121-8.361) 和 14.155 L (6.799-33.901) 。901),利福平为 5.683 L/h(3.703-7.726)和 7.736 L(6.031-8.948),利奈唑胺为 1.970 L/h(1.326-2.499)和 20.169 L(12.857-32.629)。米诺环素的观察值与预测值的最大后验概率-贝叶斯估计图的斜率为 0.999 r20.967,利福平的斜率为 0.998 r20.769,利奈唑胺的斜率为 0.998 r20.895。PK/PD 指数与临床结果无关。在利福平存在的情况下,米诺环素的转化米诺环素fAUC24h/MIC目标值>0.5,96%(49/51)的患者达到了目标值:在MRSA cSSTI患者中建立了米诺环素、利福平和利奈唑胺的人群PK模型,几乎所有患者都达到了预定义的PD指数目标。因此,AUC、MIC或AUC/MIC比值均与临床结果无关。
{"title":"Population pharmacokinetics/pharmacodynamics of minocycline plus rifampicin in patients with complicated skin and skin structure infections caused by MRSA.","authors":"Sonia Luque Pardos, William Hope, Antigone Kotsaki, Shampa Das, Evangelos J Giamarellos-Bourboulis, Theano Kontopoulouk, Karolina Akinosoglou, Miriam O'Hare, Marie L G Attwood, Karen E Bowker, Alan R Noel, Andrew M Lovering, Mark A J Bayliss, Rebecca N Evans, Alasdair P MacGowan","doi":"10.1093/jac/dkae363","DOIUrl":"https://doi.org/10.1093/jac/dkae363","url":null,"abstract":"<p><strong>Background: </strong>The population pharmacokinetics/pharmacodynamics (PK/PD) of minocycline, rifampicin and linezolid in patients with complicated skin and soft tissue infections (cSSTIs) caused by MRSA are described.</p><p><strong>Methods: </strong>Samples were collected in a Phase 4 study of oral minocycline plus rifampicin versus linezolid showing minocycline plus rifampicin to be non-inferior to linezolid. Antibiotics were assayed by HPLC or LC-MS, and a population PK model was developed using Pmetrics. The association between PK/PD indices and patient outcomes was explored.</p><p><strong>Results: </strong>A three-compartment model (with an absorption compartment) with first-order input and elimination best described the data for the three drugs. No covariates were included in the final model. The population median values (95% credibility limits) of the clearance and volume of distribution were 7.412 L/h (5.121-8.361) and 14.155 L (6.799-33.901) for minocycline, 5.683 L/h (3.703-7.726) and 7.736 L (6.031-8.948) for rifampicin, and 1.970 L/h (1.326-2.499) and 20.169 L (12.857-32.629) for linezolid, respectively. Maximum a posteriori probability-Bayesian estimation plots of observed versus predicted had a slope of 0.999 r20.967 for minocycline, slope 0.998 r20.769 for rifampicin and slope 0.998 r20.895 for linezolid. PK/PD indices were not related to clinical outcome. Taking a translational minocycline fAUC24h/MIC target of >0.5 for minocycline in the presence of rifampicin, 96% (49/51) of patients reached the target.</p><p><strong>Conclusions: </strong>Population PK models of minocycline, rifampicin and linezolid were developed in patients with MRSA cSSTI and almost all patients reached the predefined PD index targets. As a result, neither AUC, MIC nor the AUC/MIC ratio could be related to clinical outcome.</p>","PeriodicalId":14969,"journal":{"name":"Journal of Antimicrobial Chemotherapy","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466018","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}
引用次数: 0
期刊
Journal of Antimicrobial Chemotherapy
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1