Ryan K Shields, Ava J Dorazio, Giusy Tiseo, Kevin M Squires, Alessandro Leonildi, Cesira Giordano, Ellen G Kline, Simona Barnini, Alina Iovleva, Marissa P Griffith, Daria Van Tyne, Yohei Doi, Marco Falcone
{"title":"使用头孢妥珠治疗耐碳青霉烯类鲍曼不动杆菌感染的患者对头孢妥珠产生异抗性的频率。","authors":"Ryan K Shields, Ava J Dorazio, Giusy Tiseo, Kevin M Squires, Alessandro Leonildi, Cesira Giordano, Ellen G Kline, Simona Barnini, Alina Iovleva, Marissa P Griffith, Daria Van Tyne, Yohei Doi, Marco Falcone","doi":"10.1093/jacamr/dlae146","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Cefiderocol exhibits potent <i>in vitro</i> activity against carbapenem-resistant <i>Acinetobacter baumannii</i> (CRAb), but this activity has not consistently translated to improved outcomes among patients. Cefiderocol heteroresistance, or the presence of a resistant subpopulation, has been proposed as one possible explanation. The objective of this study was to explore associations between heteroresistance and outcomes of patients with CRAb infections.</p><p><strong>Methods: </strong>Baseline CRAb isolates were collected from 27 consecutive patients in the USA and Italy. Cefiderocol susceptibility was tested by broth microdilutions in triplicate. Heteroresistance was defined by population analysis profiling in duplicate. Resistance mechanisms and strain relatedness were evaluated through comparative genomic analysis.</p><p><strong>Results: </strong>Overall, 59% of infecting CRAb isolates were identified as cefiderocol-heteroresistant; rates were higher among isolates from Italy (79%) than the USA (38%). The median Charlson Comorbidity and SOFA scores were 4 and 5, respectively; 44% of patients had pneumonia, which was the most common infection type. Rates of 28-day clinical success and survival were 30% and 73%, respectively. By broth microdilution, cefiderocol MICs ≥1 mg/L were associated with higher failure rates than MICs ≤0.5 mg/L (81% versus 55%). Rates of clinical failure were numerically higher among patients infected by cefiderocol-heteroresistant compared with susceptible CRAb (81% versus 55%). Whole-genome sequencing identified a premature stop codon in the TonB<i>-</i>dependent receptor gene <i>piuA</i> in six isolates, all of which were heteroresistant.</p><p><strong>Conclusions: </strong>This pilot study supports the hypothesis that cefiderocol treatment failure may be associated with higher MICs and/or the presence of heteroresistance. Further studies are needed to confirm these findings.</p>","PeriodicalId":14594,"journal":{"name":"JAC-Antimicrobial Resistance","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11382143/pdf/","citationCount":"0","resultStr":"{\"title\":\"Frequency of cefiderocol heteroresistance among patients treated with cefiderocol for carbapenem-resistant <i>Acinetobacter baumannii</i> infections.\",\"authors\":\"Ryan K Shields, Ava J Dorazio, Giusy Tiseo, Kevin M Squires, Alessandro Leonildi, Cesira Giordano, Ellen G Kline, Simona Barnini, Alina Iovleva, Marissa P Griffith, Daria Van Tyne, Yohei Doi, Marco Falcone\",\"doi\":\"10.1093/jacamr/dlae146\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Cefiderocol exhibits potent <i>in vitro</i> activity against carbapenem-resistant <i>Acinetobacter baumannii</i> (CRAb), but this activity has not consistently translated to improved outcomes among patients. Cefiderocol heteroresistance, or the presence of a resistant subpopulation, has been proposed as one possible explanation. The objective of this study was to explore associations between heteroresistance and outcomes of patients with CRAb infections.</p><p><strong>Methods: </strong>Baseline CRAb isolates were collected from 27 consecutive patients in the USA and Italy. Cefiderocol susceptibility was tested by broth microdilutions in triplicate. Heteroresistance was defined by population analysis profiling in duplicate. Resistance mechanisms and strain relatedness were evaluated through comparative genomic analysis.</p><p><strong>Results: </strong>Overall, 59% of infecting CRAb isolates were identified as cefiderocol-heteroresistant; rates were higher among isolates from Italy (79%) than the USA (38%). The median Charlson Comorbidity and SOFA scores were 4 and 5, respectively; 44% of patients had pneumonia, which was the most common infection type. Rates of 28-day clinical success and survival were 30% and 73%, respectively. By broth microdilution, cefiderocol MICs ≥1 mg/L were associated with higher failure rates than MICs ≤0.5 mg/L (81% versus 55%). Rates of clinical failure were numerically higher among patients infected by cefiderocol-heteroresistant compared with susceptible CRAb (81% versus 55%). Whole-genome sequencing identified a premature stop codon in the TonB<i>-</i>dependent receptor gene <i>piuA</i> in six isolates, all of which were heteroresistant.</p><p><strong>Conclusions: </strong>This pilot study supports the hypothesis that cefiderocol treatment failure may be associated with higher MICs and/or the presence of heteroresistance. Further studies are needed to confirm these findings.</p>\",\"PeriodicalId\":14594,\"journal\":{\"name\":\"JAC-Antimicrobial Resistance\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2024-09-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11382143/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"JAC-Antimicrobial Resistance\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/jacamr/dlae146\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/10/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"INFECTIOUS DISEASES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"JAC-Antimicrobial Resistance","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/jacamr/dlae146","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"INFECTIOUS DISEASES","Score":null,"Total":0}
Frequency of cefiderocol heteroresistance among patients treated with cefiderocol for carbapenem-resistant Acinetobacter baumannii infections.
Background: Cefiderocol exhibits potent in vitro activity against carbapenem-resistant Acinetobacter baumannii (CRAb), but this activity has not consistently translated to improved outcomes among patients. Cefiderocol heteroresistance, or the presence of a resistant subpopulation, has been proposed as one possible explanation. The objective of this study was to explore associations between heteroresistance and outcomes of patients with CRAb infections.
Methods: Baseline CRAb isolates were collected from 27 consecutive patients in the USA and Italy. Cefiderocol susceptibility was tested by broth microdilutions in triplicate. Heteroresistance was defined by population analysis profiling in duplicate. Resistance mechanisms and strain relatedness were evaluated through comparative genomic analysis.
Results: Overall, 59% of infecting CRAb isolates were identified as cefiderocol-heteroresistant; rates were higher among isolates from Italy (79%) than the USA (38%). The median Charlson Comorbidity and SOFA scores were 4 and 5, respectively; 44% of patients had pneumonia, which was the most common infection type. Rates of 28-day clinical success and survival were 30% and 73%, respectively. By broth microdilution, cefiderocol MICs ≥1 mg/L were associated with higher failure rates than MICs ≤0.5 mg/L (81% versus 55%). Rates of clinical failure were numerically higher among patients infected by cefiderocol-heteroresistant compared with susceptible CRAb (81% versus 55%). Whole-genome sequencing identified a premature stop codon in the TonB-dependent receptor gene piuA in six isolates, all of which were heteroresistant.
Conclusions: This pilot study supports the hypothesis that cefiderocol treatment failure may be associated with higher MICs and/or the presence of heteroresistance. Further studies are needed to confirm these findings.