Aliaa Fouad, Samantha E Nicolau, Pranita D Tamma, Patricia J Simner, David P Nicolau, Christian M Gill
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Head-to-head data assessing these compounds against difficult-to-treat <i>P. aeruginosa</i> are lacking.</p><p><strong>Objectives: </strong>To assess the efficacy and resistance development of cefiderocol and ceftolozane/tazobactam in a 72-h murine thigh infection model against five clinical difficult-to-treat <i>P. aeruginosa</i> isolates susceptible for both agents and previously developed resistance to ceftolozane/tazobactam in patients.</p><p><strong>Methods: </strong>Human-simulating regimens of ceftolozane/tazobactam (2/1 g IV q8h) and cefiderocol (2 g IV q8h) were utilized. Efficacy was assessed as the change in bacterial density from starting inoculum and compared to translational endpoints of 1- and 2-log<sub>10</sub>-kill. Development of resistance was defined as a post-exposure MIC increase greater than 4-fold dilutions.</p><p><strong>Results: </strong>Cefiderocol reached the 24h 1-log<sub>10</sub>-kill endpoint in all isolates; however, ceftolozane/tazobactam reached same endpoint in 3/5 isolates. Cefiderocol reached 2-log<sub>10</sub>-kill in all isolates by 48 h. Conversely, ceftolozane/tazobactam achieved same endpoint in four isolates by 72 h. In the cefiderocol and ceftolozane/tazobactam-treated groups 17% and 8% of the cultures displayed bacterial eradication after exposure to the human-simulating regimens which hinder MIC testing for those samples. Resistance was not detected for either antibiotic postexposure.</p><p><strong>Conclusion: </strong>Despite susceptibility to both cefiderocol and ceftolozane/tazobactam, cefiderocol provided a more rapid kill profile and achieved a greater magnitude of bactericidal activity relative to ceftolozane/tazobactam. While frank resistance did not develop to either compound, differences in the rate and extent of kill were observed.</p>","PeriodicalId":73372,"journal":{"name":"Infectious diseases (London, England)","volume":" ","pages":"658-668"},"PeriodicalIF":0.0000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Comparison of the <i>in vivo</i> efficacy and resistance development potential between cefiderocol and ceftolozane/tazobactam human simulated exposures against <i>Pseudomonas aeruginosa in</i> 72-hour murine thigh infection model.\",\"authors\":\"Aliaa Fouad, Samantha E Nicolau, Pranita D Tamma, Patricia J Simner, David P Nicolau, Christian M Gill\",\"doi\":\"10.1080/23744235.2025.2471822\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong><i>Pseudomonas aeruginosa</i> with difficult-to-treat resistance is a clinical burden. Ceftolozane/tazobactam is recommended for difficult-to-treat <i>P. aeruginosa</i> although cefiderocol represents an option due to its <i>in vitro</i> potency against isolates with ceftolozane/tazobactam-resistance. Head-to-head data assessing these compounds against difficult-to-treat <i>P. aeruginosa</i> are lacking.</p><p><strong>Objectives: </strong>To assess the efficacy and resistance development of cefiderocol and ceftolozane/tazobactam in a 72-h murine thigh infection model against five clinical difficult-to-treat <i>P. aeruginosa</i> isolates susceptible for both agents and previously developed resistance to ceftolozane/tazobactam in patients.</p><p><strong>Methods: </strong>Human-simulating regimens of ceftolozane/tazobactam (2/1 g IV q8h) and cefiderocol (2 g IV q8h) were utilized. Efficacy was assessed as the change in bacterial density from starting inoculum and compared to translational endpoints of 1- and 2-log<sub>10</sub>-kill. Development of resistance was defined as a post-exposure MIC increase greater than 4-fold dilutions.</p><p><strong>Results: </strong>Cefiderocol reached the 24h 1-log<sub>10</sub>-kill endpoint in all isolates; however, ceftolozane/tazobactam reached same endpoint in 3/5 isolates. Cefiderocol reached 2-log<sub>10</sub>-kill in all isolates by 48 h. Conversely, ceftolozane/tazobactam achieved same endpoint in four isolates by 72 h. In the cefiderocol and ceftolozane/tazobactam-treated groups 17% and 8% of the cultures displayed bacterial eradication after exposure to the human-simulating regimens which hinder MIC testing for those samples. Resistance was not detected for either antibiotic postexposure.</p><p><strong>Conclusion: </strong>Despite susceptibility to both cefiderocol and ceftolozane/tazobactam, cefiderocol provided a more rapid kill profile and achieved a greater magnitude of bactericidal activity relative to ceftolozane/tazobactam. While frank resistance did not develop to either compound, differences in the rate and extent of kill were observed.</p>\",\"PeriodicalId\":73372,\"journal\":{\"name\":\"Infectious diseases (London, England)\",\"volume\":\" \",\"pages\":\"658-668\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Infectious diseases (London, England)\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1080/23744235.2025.2471822\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/3/5 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Infectious diseases (London, England)","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1080/23744235.2025.2471822","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/5 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
背景：铜绿假单胞菌耐药难治性是临床负担。Ceftolozane/他唑巴坦被推荐用于难以治疗的铜绿假单胞菌，尽管cefiderocol是一种选择，因为它对具有Ceftolozane/他唑巴坦耐药性的分离株具有体外效力。目前缺乏评估这些化合物对抗难以治疗的铜绿假单胞菌的面对面数据。目的：在小鼠大腿感染模型中，对5株临床难治性铜绿假单胞菌（P. aeruginosa， P. aeruginosa）对头孢替罗col和头孢氯氮唑/他唑巴坦敏感且既往对头孢氯氮唑/他唑巴坦耐药的患者进行72 h的疗效和耐药性评估。方法：采用头孢唑烷/他唑巴坦（2/1 g IV q8h）和头孢地罗（2 g IV q8h）模拟人体方案。从开始接种开始，与1-和2-log10-kill的翻译终点相比，通过细菌密度的变化来评估疗效。耐药性的产生被定义为暴露后MIC增加大于稀释度的4倍。结果：头孢地罗在所有分离株中均达到24h 1-log10杀伤终点；然而，头孢唑嗪/他唑巴坦在3/5的分离株中达到相同的终点。头孢地罗col在48小时内对所有分离株达到2-log10-kill。相反，头孢地罗col /他唑巴坦在72小时内对4个分离株达到了相同的终点。在头孢地罗col和头孢托ozane/他唑巴坦处理组中，17%和8%的培养物在暴露于模拟人体方案后显示细菌根除，这阻碍了这些样品的MIC测试。两种抗生素暴露后均未发现耐药性。结论：尽管对头孢地罗和头孢甲苯/他唑巴坦均有敏感性，但头孢地罗相对于头孢甲苯/他唑巴坦具有更快的杀灭效果和更强的杀菌活性。虽然对这两种化合物都没有产生明显的抗性，但在杀灭速度和程度上观察到差异。
Comparison of the in vivo efficacy and resistance development potential between cefiderocol and ceftolozane/tazobactam human simulated exposures against Pseudomonas aeruginosa in 72-hour murine thigh infection model.
Background: Pseudomonas aeruginosa with difficult-to-treat resistance is a clinical burden. Ceftolozane/tazobactam is recommended for difficult-to-treat P. aeruginosa although cefiderocol represents an option due to its in vitro potency against isolates with ceftolozane/tazobactam-resistance. Head-to-head data assessing these compounds against difficult-to-treat P. aeruginosa are lacking.
Objectives: To assess the efficacy and resistance development of cefiderocol and ceftolozane/tazobactam in a 72-h murine thigh infection model against five clinical difficult-to-treat P. aeruginosa isolates susceptible for both agents and previously developed resistance to ceftolozane/tazobactam in patients.
Methods: Human-simulating regimens of ceftolozane/tazobactam (2/1 g IV q8h) and cefiderocol (2 g IV q8h) were utilized. Efficacy was assessed as the change in bacterial density from starting inoculum and compared to translational endpoints of 1- and 2-log10-kill. Development of resistance was defined as a post-exposure MIC increase greater than 4-fold dilutions.
Results: Cefiderocol reached the 24h 1-log10-kill endpoint in all isolates; however, ceftolozane/tazobactam reached same endpoint in 3/5 isolates. Cefiderocol reached 2-log10-kill in all isolates by 48 h. Conversely, ceftolozane/tazobactam achieved same endpoint in four isolates by 72 h. In the cefiderocol and ceftolozane/tazobactam-treated groups 17% and 8% of the cultures displayed bacterial eradication after exposure to the human-simulating regimens which hinder MIC testing for those samples. Resistance was not detected for either antibiotic postexposure.
Conclusion: Despite susceptibility to both cefiderocol and ceftolozane/tazobactam, cefiderocol provided a more rapid kill profile and achieved a greater magnitude of bactericidal activity relative to ceftolozane/tazobactam. While frank resistance did not develop to either compound, differences in the rate and extent of kill were observed.
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