Christian M Gill1, Kamilia Abdelraouf1, Merime Oota2, Rio Nakamura2, Miho Kuroiwa3, Yoshinari Gahara3, Miki Takemura4, Yoshinori Yamano5, David P Nicolau1,6. 1. Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA. 2. Shionogi TechnoAdvance Research & Co., Ltd, Osaka, Japan. 3. Laboratory for Innovative Therapy Research, Shionogi & Co., Ltd, Osaka, Japan. 4. Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd, Osaka, Japan. 5. Research Planning Department, Shionogi & Co., Ltd, Osaka, Japan. 6. Division of Infectious Diseases, Hartford Hospital, Hartford, CT, USA.
Abstract
OBJECTIVES: The present study evaluated the sustained kill and the potential for resistance development of Stenotrophomonas maltophilia exposed to a human-simulated exposure of cefiderocol over 72 h in in vitro and in vivo infection models. METHODS: A total of seven S. maltophilia isolates with cefiderocol MICs of 0.03-0.5 mg/L were utilized. The sustained bactericidal activity compared with the initial inoculum and the appearance of resistance after the 72 h treatment were evaluated in both an in vitro chemostat model (four strains) and an in vivo murine thigh infection model (six strains) under the human-simulated exposure of cefiderocol (2 g every 8 h as a 3 h infusion). RESULTS: In the in vitro model, regrowth was observed for three of four tested isolates and resistance emergence (>2-dilution MIC increase) was observed for all of the four test isolates. Conversely, sustained killing over 72 h and no resistance emergence were observed for all of the six tested isolates in the in vivo models. The mechanism of all resistant isolates that appeared only in the in vitro chemostat studies was a mutation in the tonB-exbB-exbD region, which contributes to the energy transduction on the iron transporters. CONCLUSIONS: The discrepancy in the sustained efficacy and resistance emergence between in vivo and in vitro models appears to be due to the resistance acquisition mechanism caused by mutation in the tonB-exbB-exbD region developing in the enriched media utilized in vitro. These studies reveal the in vivo bactericidal activity and the low potential for development of resistance among Stenotrophomonas evaluated under human-simulated exposures.
OBJECTIVES: The present study evaluated the sustained kill and the potential for resistance development of Stenotrophomonas maltophilia exposed to a human-simulated exposure of cefiderocol over 72 h in in vitro and in vivo infection models. METHODS: A total of seven S. maltophilia isolates with cefiderocol MICs of 0.03-0.5 mg/L were utilized. The sustained bactericidal activity compared with the initial inoculum and the appearance of resistance after the 72 h treatment were evaluated in both an in vitro chemostat model (four strains) and an in vivo murine thigh infection model (six strains) under the human-simulated exposure of cefiderocol (2 g every 8 h as a 3 h infusion). RESULTS: In the in vitro model, regrowth was observed for three of four tested isolates and resistance emergence (>2-dilution MIC increase) was observed for all of the four test isolates. Conversely, sustained killing over 72 h and no resistance emergence were observed for all of the six tested isolates in the in vivo models. The mechanism of all resistant isolates that appeared only in the in vitro chemostat studies was a mutation in the tonB-exbB-exbD region, which contributes to the energy transduction on the iron transporters. CONCLUSIONS: The discrepancy in the sustained efficacy and resistance emergence between in vivo and in vitro models appears to be due to the resistance acquisition mechanism caused by mutation in the tonB-exbB-exbD region developing in the enriched media utilized in vitro. These studies reveal the in vivo bactericidal activity and the low potential for development of resistance among Stenotrophomonas evaluated under human-simulated exposures.
Authors: Brian J Werth; Nathaniel K Ashford; Kelsi Penewit; Adam Waalkes; Elizabeth A Holmes; Andrew Bryan; Stephen J Salipante Journal: JAC Antimicrob Resist Date: 2022-02-08