Open Access1058. In Vitro and In Vivo Antibacterial Activity of Cefiderocol against Burkholderia spp
Author(s) -
Merime Oota,
Hitomi Hama,
Toriko Yoshitomi,
Rio Nakamura,
Miki Takemura,
Yoshinori Yamano,
Meredith Hackel,
Daniel F. Sahm
Publication year - 2021
Publication title -
open forum infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.546
H-Index - 35
ISSN - 2328-8957
DOI - 10.1093/ofid/ofab466.1252
Subject(s) - microbiology and biotechnology , broth microdilution , burkholderia , cephalosporin , in vivo , burkholderia cepacia complex , antibiotics , minimum inhibitory concentration , agar , in vitro , antibacterial activity , medicine , biology , bacteria , biochemistry , genetics
Background Burkholderia spp. is an opportunistic pathogen associated with respiratory infections. Cefiderocol (CFDC), a siderophore cephalosporin approved in US and EU, is active in vitro against carbapenem-resistant Gram-negative bacteria including Burkholderia spp. This study examined in vitro and in vivo activity of CFDC against Burkholderia spp. Methods MICs of CFDC and 13 marketed antibacterial drugs against 462 clinical isolates of Burkholderia spp. collected in 2014 - 2019 in 13 countries were determined by broth microdilution method according to CLSI guidelines. Only for CFDC, iron-depleted CAMHB was used. In a rat lung infection model, B. cepacia ATCC 25416 (CFDC MIC: ≤ 0.031 μg/mL, MEM MIC: 4 μg/mL) was used. Male CD (SD, immunocompetent, n=4-5) rats were infected by intrabronchial inoculation of the bacterial suspension including 1% nutrient agar. The humanized PK in plasma by administration of CFDC 2 g every 8 h (3-h infusion) and MEM 1 g every 8 h (0.5-h infusion) were recreated via the continuous intravenous infusion for 4 days, and the viable cfu in lungs were counted. Results Against 462 strains, including 185 MEM non-susceptible isolates, CFDC showed MIC 50 /MIC 90 of ≤ 0.031/1 µg/mL, which was the lowest among the tested antibiotics. Among 185 MEM non-susceptible isolates, 94% of the isolates exhibited ≤ 4 µg/mL of CFDC MIC. In a rat lung infection model, CFDC and MEM showed bactericidal activity with 2.8 and 2.4 log 10 CFU/lung decrease compared with non-treated control, respectively. By recreating the humanized PK exposure in this model, 100% and ca.35% of f T >MIC of CFDC and MEM in plasma has been achieved, respectively. The bactericidal activities of both compounds vs B. cepacia ATCC 25416 would be reasonable because the f T >MIC achieved in this model exceeds the target f T >MIC (75% for CFDC and 26% for MEM against Acinetobacter baumannii , respectively) required to cause 1 log 10 reduction in murine thigh infection models 1,2) . 1) M. Sabet. 2019. AAC 2) R. Nakamura. 2019. AAC In vitro activity of CFDC and comparator agents against Burkholderia spp.Conclusion CFDC has potential for treating respiratory tract infections caused by Burkholderia spp. In critically ill patients, the recommended dosing regimen achieves 100% of f T >MIC of ≤ 4 ug/mL 3) .3) N. Kawaguchi. 2021. AAC Disclosures Merime Oota, BSc , Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Toriko Yoshitomi, -, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Rio Nakamura, BSc , Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Miki Takemura, MS , SHIONOGI & CO., LTD. (Employee) Yoshinori Yamano, PhD , Shionogi (Employee) Meredith Hackel, PhD MPH , IHMA (Employee) Pfizer, Inc. (Independent Contractor) Daniel F. Sahm, PhD , IHMA (Employee) Pfizer, Inc. (Independent Contractor)