Pub Date : 2024-10-09DOI: 10.1016/j.ijantimicag.2024.107354
Xi Wang , Qing Xie , Ying Huang, Jiansheng Lu, Lei Chen, Jiazheng Guo, Yujia Jiang, Qinglin Kang, Xinrui Yu, Wei Zhang, Meng Lv, Lingfei Hu, Rong Wang, Zhixin Yang, Tao Zheng
Drug-resistant Yersinia pestis (Y. pestis) poses a threat to the use of antibiotics to treat Y. pestis infections. Passive immunization with neutralizing monoclonal antibodies (mAbs) is considered an effective approach for the treatment of infectious diseases. In this study, a murine single-chain fragment variable (scFv) phage antibody library targeting the F1 antigen was constructed and screened. Therapeutic intravenous injection of 400 μg chimeric mAb S1 through tail veins provided complete protection against Y. pestis 201 challenge in a pneumonic plague mouse model. Timely antibody treatment eliminated the bacteria and reduced lung inflammation. These data suggest that chimeric mAb S1 is a candidate treatment for Y. pestis infection that warrants further study.
抗药性鼠疫耶尔森菌（Y. pestis）对使用抗生素治疗鼠疫耶尔森菌感染构成了威胁。使用中和单克隆抗体（mAbs）进行被动免疫是治疗传染病的一种方法。本研究构建并筛选了以F1抗原为靶标的小鼠单链片段可变（scFv）噬菌体抗体库。通过尾静脉注射 400 μg 嵌合 mAb S1，可在肺鼠疫小鼠模型中提供针对鼠疫酵母菌（菌株：91001）挑战的完全保护。及时的抗体治疗可消灭细菌并减轻肺部炎症。我们的数据表明，嵌合 mAb S1 是一种治疗鼠疫 Y. 感染的候选药物，值得进一步研究。
{"title":"Neutralizing chimeric anti-F1 monoclonal antibody against Yersinia pestis infection","authors":"Xi Wang , Qing Xie , Ying Huang, Jiansheng Lu, Lei Chen, Jiazheng Guo, Yujia Jiang, Qinglin Kang, Xinrui Yu, Wei Zhang, Meng Lv, Lingfei Hu, Rong Wang, Zhixin Yang, Tao Zheng","doi":"10.1016/j.ijantimicag.2024.107354","DOIUrl":"10.1016/j.ijantimicag.2024.107354","url":null,"abstract":"<div><div>Drug-resistant <em>Yersinia pestis</em> (<em>Y. pestis)</em> poses a threat to the use of antibiotics to treat <em>Y. pestis</em> infections. Passive immunization with neutralizing monoclonal antibodies (mAbs) is considered an effective approach for the treatment of infectious diseases. In this study, a murine single-chain fragment variable (scFv) phage antibody library targeting the F1 antigen was constructed and screened. Therapeutic intravenous injection of 400 μg chimeric mAb S1 through tail veins provided complete protection against <em>Y. pestis</em> 201 challenge in a pneumonic plague mouse model. Timely antibody treatment eliminated the bacteria and reduced lung inflammation. These data suggest that chimeric mAb S1 is a candidate treatment for <em>Y. pestis</em> infection that warrants further study.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107354"},"PeriodicalIF":4.9,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400206","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}
Pub Date : 2024-10-09DOI: 10.1016/j.ijantimicag.2024.107357
Ran Tong , Xinlei Zou , Xinge Shi , Xiaojuan Zhang , Xiang Li , Shaohua Liu , Xiaoguang Duan , Bin Han , Haixu Wang , Ruifang Zhang , Limin Sun , Yu Kong , Fen Zhang , Mingyu Ma , Xianfei Ding , Tongwen Sun
Polymyxins were applied via different administration routes to treat ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Gram-negative bacteria (CR-GNB). The potential benefits of aerosolised polymyxins as adjunctive treatment for patients are contradictory. This review assessed the safety and efficacy of intravenous (IV) combined with aerosolised polymyxins vs IV polymyxins monotherapy in patients with VAP caused by CR-GNB. Two reviewers independently evaluated and extracted data from PubMed, Embase, Cochrane library and Web of Science. The primary outcome was all-cause mortality and secondary outcomes included clinical cure rate, clinical improvement rate, microbiological eradication rate and nephrotoxicity. Differences for dichotomous outcomes were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Eleven eligible studies were included. The results showed that compared with IV polymyxins monotherapy, IV plus aerosolised polymyxins therapy significantly reduced all-cause mortality rate (OR = 0.75, 95% CI 0.57–0.99, P = 0.045) and improved clinical improvement rate (OR = 1.62, 95% CI 1.02–2.60, P = 0.043) and microbial eradication rate (OR = 2.07, 95% CI 1.40–3.05, P = 0.000). However, there were no significant differences in terms of clinical cure rate (OR = 1.59, 95% CI 0.96–2.63, P = 0.072) and nephrotoxicity (OR = 1.14, 95% CI 0.80–1.63, P = 0.467) for IV plus aerosolised polymyxins therapy. Subgroup analysis revealed that the clinical improvement rate was significantly improved in case-control studies. Aerosolised polymyxins may be a useful adjunct to IV polymyxins for patients with CR-GNB VAP.
多粘菌素通过不同的给药途径用于治疗由耐碳青霉烯类革兰氏阴性菌（CR-GNB）引起的呼吸机相关肺炎（VAP）。气雾多粘菌素作为辅助治疗手段对患者的潜在益处仍存在矛盾。本综述评估了在 CR-GNB 引起的 VAP 患者中，静脉联合气雾化多粘菌素与静脉单用多粘菌素治疗的安全性和有效性。两名审稿人从 Pubmed、Embase、Cochrane 图书馆和 Web of science 中独立评估和提取了相关数据。主要结果为全因死亡率，次要结果包括临床治愈率、临床改善率、微生物根除率和肾毒性。二分结果的差异以几率比（OR）和 95% 置信区间（CI）表示。共纳入了 11 项符合条件的研究。结果显示，与静脉注射多粘菌素单一疗法相比，静脉注射加气雾化多粘菌素疗法可显著降低全因死亡率（OR = 0.75，95% CI 0.57 - 0.99，P = 0.045），提高临床改善率（OR = 1.62，95% CI 1.02 - 2.60，P = 0.043）和微生物根除率（OR = 2.07，95% CI 1.40 - 3.05，P = 0.000）。然而，静脉注射加气雾多粘菌素疗法在临床治愈率（OR = 1.59，95% CI 0.96 - 2.63，P = 0.072）和肾毒性（OR = 1.14，95% CI 0.80 - 1.63，P = 0.467）方面没有明显差异。亚组分析显示，病例对照研究中的临床改善率明显提高。对于 CR-GNB VAP 患者来说，气雾化多粘菌素可能是静脉注射多粘菌素的有效辅助疗法。
{"title":"Intravenous combined with aerosolised polymyxins vs intravenous polymyxins monotherapy for ventilator-associated pneumonia: A systematic review and meta-analysis","authors":"Ran Tong , Xinlei Zou , Xinge Shi , Xiaojuan Zhang , Xiang Li , Shaohua Liu , Xiaoguang Duan , Bin Han , Haixu Wang , Ruifang Zhang , Limin Sun , Yu Kong , Fen Zhang , Mingyu Ma , Xianfei Ding , Tongwen Sun","doi":"10.1016/j.ijantimicag.2024.107357","DOIUrl":"10.1016/j.ijantimicag.2024.107357","url":null,"abstract":"<div><div>Polymyxins were applied via different administration routes to treat ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Gram-negative bacteria (CR-GNB). The potential benefits of aerosolised polymyxins as adjunctive treatment for patients are contradictory. This review assessed the safety and efficacy of intravenous (IV) combined with aerosolised polymyxins vs IV polymyxins monotherapy in patients with VAP caused by CR-GNB. Two reviewers independently evaluated and extracted data from PubMed, Embase, Cochrane library and Web of Science. The primary outcome was all-cause mortality and secondary outcomes included clinical cure rate, clinical improvement rate, microbiological eradication rate and nephrotoxicity. Differences for dichotomous outcomes were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Eleven eligible studies were included. The results showed that compared with IV polymyxins monotherapy, IV plus aerosolised polymyxins therapy significantly reduced all-cause mortality rate (OR = 0.75, 95% CI 0.57–0.99, <em>P</em> = 0.045) and improved clinical improvement rate (OR = 1.62, 95% CI 1.02–2.60, <em>P</em> = 0.043) and microbial eradication rate (OR = 2.07, 95% CI 1.40–3.05, <em>P</em> = 0.000). However, there were no significant differences in terms of clinical cure rate (OR = 1.59, 95% CI 0.96–2.63, <em>P</em> = 0.072) and nephrotoxicity (OR = 1.14, 95% CI 0.80–1.63, <em>P</em> = 0.467) for IV plus aerosolised polymyxins therapy. Subgroup analysis revealed that the clinical improvement rate was significantly improved in case-control studies. Aerosolised polymyxins may be a useful adjunct to IV polymyxins for patients with CR-GNB VAP.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107357"},"PeriodicalIF":4.9,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400205","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}
Pub Date : 2024-10-01DOI: 10.1016/j.ijantimicag.2024.107353
Fatima I. Darwiche , Hadi M. Hussein , Souad Bou Harb , Sarah Nahhal , Abdallah Kurdi , Ahmad Sleiman , Lama Hamadeh , Sara Barada , Jose-Rita Gerges , George F. Araj , Nada Kara Zahreddine , Ahmad Ibrahim , Zeina Kanafani , Rami Mahfouz , Souha S. Kanj , Ghassan M. Matar , Antoine G. Abou Fayad
The frequent occurrence of Acinetobacter baumannii in hospital settings and the elevated rate of antimicrobial resistance in this pathogen represent a serious clinical and public health threat worldwide, and particularly in Lebanon where outbreak surveillance and control are still insufficient. Whole-genome sequencing (WGS) is a fast and reliable tool to study outbreaks at the molecular level and obtain actionable knowledge, leading to better control measures. A total of 59 A. baumannii isolates were collected from intensive care unit (ICU) patients (57 isolates) and from the hospital environment (2 isolates) between August 2022 and May 2023, antimicrobial susceptibility testing (AST) was performed and gDNA was subjected to WGS. Analysis was performed to reveal the sequence types (ST), the relatedness to strains that caused other outbreaks and the arsenal of resistance genes harboured by these bacteria. Of 59 isolates, 85% were categorised as extensively drug-resistant (XDR), 13.6% as multidrug-resistant (MDR) and 1.7% as pan-drug-resistant. All isolates belonged to international clone (IC)2, of which the majority were of ST2 (91.5%). The isolates clustered well with those of a previous outbreak in the same hospital. In addition, isolates from hospitals in Lebanon clustered well together and some clustered with those originating from other countries. The observed genetic relatedness between the current isolates and those from the previous outbreaks underscores the importance of strict surveillance to limit the threat of outbreaks. Moreover, the clustering of isolates from Lebanon with others from distant countries proves the necessity to further investigate the international spread of drug-resistant pathogens and the implementation of control strategies.
{"title":"Investigating an Outbreak of Extensively Drug-Resistant Acinetobacter baumannii in a Tertiary Healthcare Centre in Lebanon Using Next-Generation Sequencing","authors":"Fatima I. Darwiche , Hadi M. Hussein , Souad Bou Harb , Sarah Nahhal , Abdallah Kurdi , Ahmad Sleiman , Lama Hamadeh , Sara Barada , Jose-Rita Gerges , George F. Araj , Nada Kara Zahreddine , Ahmad Ibrahim , Zeina Kanafani , Rami Mahfouz , Souha S. Kanj , Ghassan M. Matar , Antoine G. Abou Fayad","doi":"10.1016/j.ijantimicag.2024.107353","DOIUrl":"10.1016/j.ijantimicag.2024.107353","url":null,"abstract":"<div><div>The frequent occurrence of <em>Acinetobacter baumannii</em> in hospital settings and the elevated rate of antimicrobial resistance in this pathogen represent a serious clinical and public health threat worldwide, and particularly in Lebanon where outbreak surveillance and control are still insufficient. Whole-genome sequencing (WGS) is a fast and reliable tool to study outbreaks at the molecular level and obtain actionable knowledge, leading to better control measures. A total of 59 <em>A. baumannii</em> isolates were collected from intensive care unit (ICU) patients (57 isolates) and from the hospital environment (2 isolates) between August 2022 and May 2023, antimicrobial susceptibility testing (AST) was performed and gDNA was subjected to WGS. Analysis was performed to reveal the sequence types (ST), the relatedness to strains that caused other outbreaks and the arsenal of resistance genes harboured by these bacteria. Of 59 isolates, 85% were categorised as extensively drug-resistant (XDR), 13.6% as multidrug-resistant (MDR) and 1.7% as pan-drug-resistant. All isolates belonged to international clone (IC)2, of which the majority were of ST2 (91.5%). The isolates clustered well with those of a previous outbreak in the same hospital. In addition, isolates from hospitals in Lebanon clustered well together and some clustered with those originating from other countries. The observed genetic relatedness between the current isolates and those from the previous outbreaks underscores the importance of strict surveillance to limit the threat of outbreaks. Moreover, the clustering of isolates from Lebanon with others from distant countries proves the necessity to further investigate the international spread of drug-resistant pathogens and the implementation of control strategies.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 5","pages":"Article 107353"},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371768","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}
Pub Date : 2024-10-01DOI: 10.1016/j.ijantimicag.2024.107343
Gabriele Bianco , Matteo Boattini , Sara Comini , Davide Gibellini , Paolo Gaibani
{"title":"In Vivo Emergence of Ceftazidime/Avibactam, Cefiderocol and Aztreonam/Avibactam Cross-Resistance in a Patient With KPC-Producing Klebsiella pneumoniae Infection After Cefiderocol-Based Treatment","authors":"Gabriele Bianco , Matteo Boattini , Sara Comini , Davide Gibellini , Paolo Gaibani","doi":"10.1016/j.ijantimicag.2024.107343","DOIUrl":"10.1016/j.ijantimicag.2024.107343","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 5","pages":"Article 107343"},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371767","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}
Pub Date : 2024-10-01DOI: 10.1016/j.ijantimicag.2024.107351
Simone Lanini , Simone Giuliano , Jacopo Angelini , Sara Ferin , Luca Martini , Massimo Baraldo , Stella Cossettini , Jason Roberts , Carlo Tascini
Objective
This study measured the effect of renal function on the plasma concentrations of ceftazidime and avibactam in critically ill patients. We also sought to measure the concentration ratio of ceftazidime to avibactam.
Methods
This was a cohort study at a tertiary referral centre in Italy, on patients treated with continuous infusion of ceftazidime-avibactam (CAZ-AVI) between November 2019 and December 2023. The association between creatine clearance (CrCl) and free plasma ceftazidime and avibactam concentration, as well as CAZ-AVI ratio was explored to assess correlation and potential risk to fail to achieve target therapeutic concentration.
Results
Fifty-two patients, predominantly male (75%), with a median age of 68.5 y were included. Our analyses provided strong evidence for inverse correlation between CrCl and both free-CAZ (r = -0.627; R2 = 0.3936; P < 0.001) and free-AVI plasma concentration (r = -0.619; R2 = 0.3832; P < 0.001). Overall CrCl alone could explain about 40% of overall variation of either free-CAZ and free-AVI. Linear models suggest that free-CAZ and free-AVI concentration drop of about 7.31% and 9.23% for each 10 point increase of CrCl, respectively. Assessment of the CAZ-AVI ratio supports a direct linear association with CrCl suggesting that free-AVI concentration is more affected by CrCl variation than free-CAZ concentration. Patients with CrCl ≥130 mL/min showed a significantly higher risk of suboptimal drug exposure (i.e., less than 4 times the MIC) both to CAZ and AVI.
Conclusion
The findings emphasise the need for individualised dosing strategies of CAZ-AVI based on renal function, for antibiotics used in critically ill patients. The study suggests that underdosing in patients with high CrCl is likely to be common and as such could affect drug effectiveness.
{"title":"Renal function and its impact on the concentration of ceftazidime-avibactam: A cross-sectional study","authors":"Simone Lanini , Simone Giuliano , Jacopo Angelini , Sara Ferin , Luca Martini , Massimo Baraldo , Stella Cossettini , Jason Roberts , Carlo Tascini","doi":"10.1016/j.ijantimicag.2024.107351","DOIUrl":"10.1016/j.ijantimicag.2024.107351","url":null,"abstract":"<div><h3>Objective</h3><div>This study measured the effect of renal function on the plasma concentrations of ceftazidime and avibactam in critically ill patients. We also sought to measure the concentration ratio of ceftazidime to avibactam.</div></div><div><h3>Methods</h3><div>This was a cohort study at a tertiary referral centre in Italy, on patients treated with continuous infusion of ceftazidime-avibactam (CAZ-AVI) between November 2019 and December 2023. The association between creatine clearance (CrCl) and free plasma ceftazidime and avibactam concentration, as well as CAZ-AVI ratio was explored to assess correlation and potential risk to fail to achieve target therapeutic concentration.</div></div><div><h3>Results</h3><div>Fifty-two patients, predominantly male (75%), with a median age of 68.5 y were included. Our analyses provided strong evidence for inverse correlation between CrCl and both free-CAZ (<em>r</em> = -0.627; <em>R<sup>2</sup></em> = 0.3936; <em>P</em> < 0.001) and free-AVI plasma concentration (<em>r</em> = -0.619; <em>R</em><sup>2</sup> = 0.3832; <em>P</em> < 0.001). Overall CrCl alone could explain about 40% of overall variation of either free-CAZ and free-AVI. Linear models suggest that free-CAZ and free-AVI concentration drop of about 7.31% and 9.23% for each 10 point increase of CrCl, respectively. Assessment of the CAZ-AVI ratio supports a direct linear association with CrCl suggesting that free-AVI concentration is more affected by CrCl variation than free-CAZ concentration. Patients with CrCl ≥130 mL/min showed a significantly higher risk of suboptimal drug exposure (i.e., less than 4 times the MIC) both to CAZ and AVI.</div></div><div><h3>Conclusion</h3><div>The findings emphasise the need for individualised dosing strategies of CAZ-AVI based on renal function, for antibiotics used in critically ill patients. The study suggests that underdosing in patients with high CrCl is likely to be common and as such could affect drug effectiveness.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107351"},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371769","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}
Pub Date : 2024-09-28DOI: 10.1016/j.ijantimicag.2024.107352
Salma M. Bahnasawy , Neil J. Parrott , Matthias Gijsen , Isabel Spriet , Lena E. Friberg , Elisabet I. Nielsen
Objectives
Applying physiologically-based pharmacokinetic (PBPK) modelling in sepsis could help to better understand how PK changes are influenced by drug- and patient-related factors. We aimed to elucidate the influence of sepsis pathophysiology on the PK of meropenem by applying PBPK modelling.
Methods
A whole-body meropenem PBPK model was developed and evaluated in healthy individuals, and renally impaired non-septic patients. Sepsis-induced physiological changes in body composition, organ blood flow, kidney function, albumin, and haematocrit were implemented according to a previously proposed PBPK sepsis model. Model performance was evaluated, and a local sensitivity analysis was conducted.
Results
The model-predicted PK metrics (AUC, Cmax, CL, Vss) were within 1.33-fold-error margin of published data for 87.5% of the simulated profiles in healthy individuals. In sepsis, the model provided good predictions for literature-digitised average plasma and tissue exposure data, where the model-predicted AUC was within 1.33-fold-error margin for 9 out 11 simulated study profiles. Furthermore, the model was applied to individual plasma concentration data from 52 septic patients, where the model-predicted AUC, Cmax, and CL had a fold-error ratio range of 0.98–1.12, with alignment of the predicted and observed variability. For Vss, the fold-error ratio was 0.81, and the model underpredicted the population variability. CL was sensitive to renal plasma clearance, and kidney volume, whereas Vss was sensitive to the unbound fraction, organ volume fraction of the interstitial compartment, and the organ volume.
Conclusions
These findings may be extended to more diverse drug types and support a more mechanistic understanding of the effect of sepsis on drug exposure.
{"title":"Physiologically-based pharmacokinetic modelling in sepsis: A tool to elucidate how pathophysiology affects meropenem pharmacokinetics","authors":"Salma M. Bahnasawy , Neil J. Parrott , Matthias Gijsen , Isabel Spriet , Lena E. Friberg , Elisabet I. Nielsen","doi":"10.1016/j.ijantimicag.2024.107352","DOIUrl":"10.1016/j.ijantimicag.2024.107352","url":null,"abstract":"<div><h3>Objectives</h3><div>Applying physiologically-based pharmacokinetic (PBPK) modelling in sepsis could help to better understand how PK changes are influenced by drug- and patient-related factors. We aimed to elucidate the influence of sepsis pathophysiology on the PK of meropenem by applying PBPK modelling.</div></div><div><h3>Methods</h3><div>A whole-body meropenem PBPK model was developed and evaluated in healthy individuals, and renally impaired non-septic patients. Sepsis-induced physiological changes in body composition, organ blood flow, kidney function, albumin, and haematocrit were implemented according to a previously proposed PBPK sepsis model. Model performance was evaluated, and a local sensitivity analysis was conducted.</div></div><div><h3>Results</h3><div>The model-predicted PK metrics (AUC, C<sub>max</sub>, CL, V<sub>ss</sub>) were within 1.33-fold-error margin of published data for 87.5% of the simulated profiles in healthy individuals. In sepsis, the model provided good predictions for literature-digitised average plasma and tissue exposure data, where the model-predicted AUC was within 1.33-fold-error margin for 9 out 11 simulated study profiles. Furthermore, the model was applied to individual plasma concentration data from 52 septic patients, where the model-predicted AUC, C<sub>max</sub>, and CL had a fold-error ratio range of 0.98–1.12, with alignment of the predicted and observed variability. For V<sub>ss</sub>, the fold-error ratio was 0.81, and the model underpredicted the population variability. CL was sensitive to renal plasma clearance, and kidney volume, whereas V<sub>ss</sub> was sensitive to the unbound fraction, organ volume fraction of the interstitial compartment, and the organ volume.</div></div><div><h3>Conclusions</h3><div>These findings may be extended to more diverse drug types and support a more mechanistic understanding of the effect of sepsis on drug exposure.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107352"},"PeriodicalIF":4.9,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346072","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}
Pub Date : 2024-09-27DOI: 10.1016/j.ijantimicag.2024.107350
Fábio Parra Sellera , Yilu Zhuang , Nilton Lincopan , Eliana Guedes Stehling , Sergio Schenkman , Zhi Ruan , João Pedro Rueda Furlan
{"title":"Genomic tracking the coexistence of mcr and carbapenemase genes in Gram-negative bacteria: a global perspective","authors":"Fábio Parra Sellera , Yilu Zhuang , Nilton Lincopan , Eliana Guedes Stehling , Sergio Schenkman , Zhi Ruan , João Pedro Rueda Furlan","doi":"10.1016/j.ijantimicag.2024.107350","DOIUrl":"10.1016/j.ijantimicag.2024.107350","url":null,"abstract":"","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 5","pages":"Article 107350"},"PeriodicalIF":4.9,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346170","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}
Pub Date : 2024-09-26DOI: 10.1016/j.ijantimicag.2024.107346
Xiaojun Cai , Yan Chen , Jing Fu , Yaojie Chen , Lingzhi Shi , Chuang Chen , Chunhong Zhang , Shufang Zhou , Wenbo Zhou , Bo Wu , Hang Yang , Xuben Yu
Objective
Currently, there is a lack of information on the clinical pharmacokinetics (PK), effectiveness, and safety of colistin sulphate (CS) in lung transplant recipients. This study aims to improve CS dosing regimens and evaluate its population PK in lung transplant recipients.
Methods
This study evaluated the clinical efficacy, microbiological efficacy, and adverse events of CS in lung transplant recipients. The NONMEM program was employed to construct the population PK model, and Monte Carlo simulations were executed to establish dosing regimens according to the probability of target attainment (PTA).
Results
The study included 146 CS concentrations, spanning from 0.05 to 4.18 mg/L from 39 lung transplant recipients with multidrug-resistant Gram-negative bacteria. 26 (66.67%) patients successfully eradicated bacteria, and 30 (76.92%) patients had clinical cure or improvement. Additionally, only 2 (5.13%) patients developed CS-related nephrotoxicity. The PK profile was effectively represented by a one-compartmental model with linear elimination. Creatinine clearance and concomitant furosemide use were recognized as covariates influencing the clearance of CS. Based on the PTA results, a daily dosage of 1.5 million IU, divided into 2–3 administrations, could attain a PTA exceeding 90% for MIC ≤ 1 µg/mL at creatinine clearance of about 110 mL/min. However, this regimen would lead to insufficient exposure for MIC ≥ 2 µg/mL.
Conclusions
The clearance of CS is significantly influenced by concomitant furosemide use and renal function. The currently recommended dosing regimens by label sheet may result in subtherapeutic exposure for MIC exceeding 1 mg/L in lung transplant recipients.
{"title":"Population pharmacokinetic analysis and dosing optimization of colistin sulphate in lung transplant recipients with pneumonia: A prospective study","authors":"Xiaojun Cai , Yan Chen , Jing Fu , Yaojie Chen , Lingzhi Shi , Chuang Chen , Chunhong Zhang , Shufang Zhou , Wenbo Zhou , Bo Wu , Hang Yang , Xuben Yu","doi":"10.1016/j.ijantimicag.2024.107346","DOIUrl":"10.1016/j.ijantimicag.2024.107346","url":null,"abstract":"<div><h3>Objective</h3><div>Currently, there is a lack of information on the clinical pharmacokinetics (PK), effectiveness, and safety of colistin sulphate (CS) in lung transplant recipients. This study aims to improve CS dosing regimens and evaluate its population PK in lung transplant recipients.</div></div><div><h3>Methods</h3><div>This study evaluated the clinical efficacy, microbiological efficacy, and adverse events of CS in lung transplant recipients. The NONMEM program was employed to construct the population PK model, and Monte Carlo simulations were executed to establish dosing regimens according to the probability of target attainment (PTA).</div></div><div><h3>Results</h3><div>The study included 146 CS concentrations, spanning from 0.05 to 4.18 mg/L from 39 lung transplant recipients with multidrug-resistant Gram-negative bacteria. 26 (66.67%) patients successfully eradicated bacteria, and 30 (76.92%) patients had clinical cure or improvement. Additionally, only 2 (5.13%) patients developed CS-related nephrotoxicity. The PK profile was effectively represented by a one-compartmental model with linear elimination. Creatinine clearance and concomitant furosemide use were recognized as covariates influencing the clearance of CS. Based on the PTA results, a daily dosage of 1.5 million IU, divided into 2–3 administrations, could attain a PTA exceeding 90% for MIC ≤ 1 µg/mL at creatinine clearance of about 110 mL/min. However, this regimen would lead to insufficient exposure for MIC ≥ 2 µg/mL.</div></div><div><h3>Conclusions</h3><div>The clearance of CS is significantly influenced by concomitant furosemide use and renal function. The currently recommended dosing regimens by label sheet may result in subtherapeutic exposure for MIC exceeding 1 mg/L in lung transplant recipients.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 5","pages":"Article 107346"},"PeriodicalIF":4.9,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346073","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}
Pub Date : 2024-09-23DOI: 10.1016/j.ijantimicag.2024.107345
Ruoying Zhang , Junke Qiu , Feng Zhou , Junjie Cheng , Xudong Fan , Chenxi Yan , Ren Zheng , Xinjun Cai , Jinmeng Li
Continuous kidney replacement therapy (CRRT) is a special form of dialysis, which has more significant advantages than traditional intermittent hemodialysis in treating critically ill patients. The impact of CRRT and disease complexity on drug clearance in critically ill patients has been reported in several studies; nevertheless, the pharmacokinetic changes of cycloserine in patients with sepsis undergoing CRRT have not been reported. Here, we report a case of a 52-year-old man with septic shock and severe multidrug-resistant tuberculosis who underwent anti-tuberculosis (anti-TB) therapy. The patient's anti-TB regimen included linezolid, clofazimine, cycloserine, and bedaquiline. Following continuous administration for 14 days, the patient was treated with CRRT due to acid–base imbalance and acute renal failure. Blood samples were collected at 0, 2, 4, 6, 10, and 12 hours following cycloserine administration (CRRT was initiated 2 hours after administration). Changes in plasma concentration of cycloserine before and after CRRT were measured. The peak concentration of cycloserine was 39.93 mg/L with a trough concentration of 7.90 mg/L, and the AUC0-12h was 294.36 mg·h/L. These findings suggest that the pharmacokinetics of cycloserine may be influenced by sepsis and CRRT therapy, and that cycloserine doses may need to be increased during CRRT therapy in patients with sepsis.
{"title":"Challenges and Potential Solutions for Cycloserine Dosing in Patients With Sepsis Undergoing Continuous Renal Replacement Therapy","authors":"Ruoying Zhang , Junke Qiu , Feng Zhou , Junjie Cheng , Xudong Fan , Chenxi Yan , Ren Zheng , Xinjun Cai , Jinmeng Li","doi":"10.1016/j.ijantimicag.2024.107345","DOIUrl":"10.1016/j.ijantimicag.2024.107345","url":null,"abstract":"<div><div>Continuous kidney replacement therapy (CRRT) is a special form of dialysis, which has more significant advantages than traditional intermittent hemodialysis in treating critically ill patients. The impact of CRRT and disease complexity on drug clearance in critically ill patients has been reported in several studies; nevertheless, the pharmacokinetic changes of cycloserine in patients with sepsis undergoing CRRT have not been reported. Here, we report a case of a 52-year-old man with septic shock and severe multidrug-resistant tuberculosis who underwent anti-tuberculosis (anti-TB) therapy. The patient's anti-TB regimen included linezolid, clofazimine, cycloserine, and bedaquiline. Following continuous administration for 14 days, the patient was treated with CRRT due to acid–base imbalance and acute renal failure. Blood samples were collected at 0, 2, 4, 6, 10, and 12 hours following cycloserine administration (CRRT was initiated 2 hours after administration). Changes in plasma concentration of cycloserine before and after CRRT were measured. The peak concentration of cycloserine was 39.93 mg/L with a trough concentration of 7.90 mg/L, and the AUC<sub>0-12h</sub> was 294.36 mg·h/L. These findings suggest that the pharmacokinetics of cycloserine may be influenced by sepsis and CRRT therapy, and that cycloserine doses may need to be increased during CRRT therapy in patients with sepsis.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 5","pages":"Article 107345"},"PeriodicalIF":4.9,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346168","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}
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