Lisa Allander, Emma Vikdahl, Margarita Chatzopoulou, Amaury O'Jeanson, Linus Sandegren, Pernilla Lagerbäck, Thomas Tängdén
{"title":"头孢他啶/阿维巴坦联合粘菌素对产kpc -2肺炎克雷伯菌的静态和动态时间杀伤实验评价","authors":"Lisa Allander, Emma Vikdahl, Margarita Chatzopoulou, Amaury O'Jeanson, Linus Sandegren, Pernilla Lagerbäck, Thomas Tängdén","doi":"10.1093/jacamr/dlaf105","DOIUrl":null,"url":null,"abstract":"<p><strong>Objectives: </strong>Ceftazidime/avibactam is used for severe infections caused by carbapenemase-producing <i>Klebsiella pneumoniae</i>. Combination therapy with older antibiotics is frequently used, but the supporting data are limited. This study aimed to evaluate ceftazidime/avibactam in combination with colistin against KPC-2-producing <i>K. pneumoniae</i>.</p><p><strong>Material and methods: </strong>Five clinical KPC-2-producing <i>K. pneumoniae</i> strains were characterized by phenotypic antibiotic susceptibility testing and whole-genome sequencing. Single antibiotics and combinations were evaluated in 24-h static time-kill experiments with ceftazidime/avibactam concentrations of 0.5× MIC<sub>ratio</sub> and colistin at 0.5× and 1× MIC. One strain was subjected to 32-h dynamic time-kill experiments with ceftazidime/avibactam at concentrations mimicking patient pharmacokinetics in plasma and colistin added to 1 mg/L, i.e. the average free steady-state concentration. Population analysis was performed at 0, 16, and 32 h by plating at 4× and 8× MIC<sub>ratio</sub> (ceftazidime/avibactam) or MIC (colistin) to assess resistance development.</p><p><strong>Results: </strong>All strains were susceptible to ceftazidime/avibactam and colistin, had mutations in <i>ompK35</i> and <i>ompK36</i>, and carried multiple β-lactamase genes. Ceftazidime/avibactam combined with colistin demonstrated 24-h synergy in static time-kill experiments against 3 of 5 strains. Although ceftazidime/avibactam and colistin alone showed rapid initial killing in the dynamic experiments, regrowth occurred after 4-8 h. The three-drug combination displayed a bactericidal effect and synergy at 14-32 h. Resistance development resulting in 64-fold MIC increases was observed in experiments with colistin alone.</p><p><strong>Conclusions: </strong>This study showed synergy with ceftazidime/avibactam and colistin against KPC-2-producing <i>K. pneumoniae</i> at clinically relevant concentrations. More studies are warranted to investigate the clinical potential of this combination.</p>","PeriodicalId":14594,"journal":{"name":"JAC-Antimicrobial Resistance","volume":"7 3","pages":"dlaf105"},"PeriodicalIF":3.3000,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203663/pdf/","citationCount":"0","resultStr":"{\"title\":\"Evaluation of ceftazidime/avibactam in combination with colistin against KPC-2-producing <i>Klebsiella pneumoniae</i> in static and dynamic time-kill experiments.\",\"authors\":\"Lisa Allander, Emma Vikdahl, Margarita Chatzopoulou, Amaury O'Jeanson, Linus Sandegren, Pernilla Lagerbäck, Thomas Tängdén\",\"doi\":\"10.1093/jacamr/dlaf105\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objectives: </strong>Ceftazidime/avibactam is used for severe infections caused by carbapenemase-producing <i>Klebsiella pneumoniae</i>. Combination therapy with older antibiotics is frequently used, but the supporting data are limited. This study aimed to evaluate ceftazidime/avibactam in combination with colistin against KPC-2-producing <i>K. pneumoniae</i>.</p><p><strong>Material and methods: </strong>Five clinical KPC-2-producing <i>K. pneumoniae</i> strains were characterized by phenotypic antibiotic susceptibility testing and whole-genome sequencing. Single antibiotics and combinations were evaluated in 24-h static time-kill experiments with ceftazidime/avibactam concentrations of 0.5× MIC<sub>ratio</sub> and colistin at 0.5× and 1× MIC. One strain was subjected to 32-h dynamic time-kill experiments with ceftazidime/avibactam at concentrations mimicking patient pharmacokinetics in plasma and colistin added to 1 mg/L, i.e. the average free steady-state concentration. Population analysis was performed at 0, 16, and 32 h by plating at 4× and 8× MIC<sub>ratio</sub> (ceftazidime/avibactam) or MIC (colistin) to assess resistance development.</p><p><strong>Results: </strong>All strains were susceptible to ceftazidime/avibactam and colistin, had mutations in <i>ompK35</i> and <i>ompK36</i>, and carried multiple β-lactamase genes. Ceftazidime/avibactam combined with colistin demonstrated 24-h synergy in static time-kill experiments against 3 of 5 strains. Although ceftazidime/avibactam and colistin alone showed rapid initial killing in the dynamic experiments, regrowth occurred after 4-8 h. The three-drug combination displayed a bactericidal effect and synergy at 14-32 h. Resistance development resulting in 64-fold MIC increases was observed in experiments with colistin alone.</p><p><strong>Conclusions: </strong>This study showed synergy with ceftazidime/avibactam and colistin against KPC-2-producing <i>K. pneumoniae</i> at clinically relevant concentrations. More studies are warranted to investigate the clinical potential of this combination.</p>\",\"PeriodicalId\":14594,\"journal\":{\"name\":\"JAC-Antimicrobial Resistance\",\"volume\":\"7 3\",\"pages\":\"dlaf105\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2025-06-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203663/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"JAC-Antimicrobial Resistance\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/jacamr/dlaf105\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/6/1 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/dlaf105","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"INFECTIOUS DISEASES","Score":null,"Total":0}
Evaluation of ceftazidime/avibactam in combination with colistin against KPC-2-producing Klebsiella pneumoniae in static and dynamic time-kill experiments.
Objectives: Ceftazidime/avibactam is used for severe infections caused by carbapenemase-producing Klebsiella pneumoniae. Combination therapy with older antibiotics is frequently used, but the supporting data are limited. This study aimed to evaluate ceftazidime/avibactam in combination with colistin against KPC-2-producing K. pneumoniae.
Material and methods: Five clinical KPC-2-producing K. pneumoniae strains were characterized by phenotypic antibiotic susceptibility testing and whole-genome sequencing. Single antibiotics and combinations were evaluated in 24-h static time-kill experiments with ceftazidime/avibactam concentrations of 0.5× MICratio and colistin at 0.5× and 1× MIC. One strain was subjected to 32-h dynamic time-kill experiments with ceftazidime/avibactam at concentrations mimicking patient pharmacokinetics in plasma and colistin added to 1 mg/L, i.e. the average free steady-state concentration. Population analysis was performed at 0, 16, and 32 h by plating at 4× and 8× MICratio (ceftazidime/avibactam) or MIC (colistin) to assess resistance development.
Results: All strains were susceptible to ceftazidime/avibactam and colistin, had mutations in ompK35 and ompK36, and carried multiple β-lactamase genes. Ceftazidime/avibactam combined with colistin demonstrated 24-h synergy in static time-kill experiments against 3 of 5 strains. Although ceftazidime/avibactam and colistin alone showed rapid initial killing in the dynamic experiments, regrowth occurred after 4-8 h. The three-drug combination displayed a bactericidal effect and synergy at 14-32 h. Resistance development resulting in 64-fold MIC increases was observed in experiments with colistin alone.
Conclusions: This study showed synergy with ceftazidime/avibactam and colistin against KPC-2-producing K. pneumoniae at clinically relevant concentrations. More studies are warranted to investigate the clinical potential of this combination.
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