Evaluation of ceftriaxone plus avibactam in an intracellular hollow fiber model of tuberculosis: implications for the treatment of disseminated and meningeal tuberculosis in children
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Background:
Ceftazidime-avibactam is an effective agent for the treatment of tuberculosis (TB) but requires frequent administration because of a short half-life. Due to a longer half-life, ceftriaxone could allow intermittent dosing.
Methods:
First, we identified the MIC of ceftriaxone with 15 mg/L avibactam in 30 clinical Mycobacterium tuberculosis isolates. Next, 2 ceftriaxone exposure-effect studies in the intracellular hollow fiber model of TB (HFS-TB) that mimics disseminated disease in young children, were performed. Ceftriaxone was administered once or twice daily for 28 days to explore percentage of time that the concentration persisted above MIC (%TMIC) ranging from 0 to 100%. In a third HFS-TB experiment, the “double cephalosporin” regimen of ceftazidime-ceftriaxone-avibactam was examined and analyzed using Bliss Independence.
Conclusion:
The MIC99 of the clinical strains was 32 mg/L, in the presence of 15 mg/L avibactam. Ceftriaxone %TMIC <42 had no microbial effect in the HFS-TB, %TMIC>54% demonstrated a 4.1 log10 colony-forming units per milliliter M. tuberculosis kill, while %TMIC mediating Emax was 68%. The “double cephalosporin” combination was highly synergistic. Monte Carlo experiments of 10,000 subjects identified the optimal ceftriaxone dose as 100 mg/kg twice a day.
Conclusion:
The combination of ceftriaxone-avibactam at 100 mg/kg could achieve Emax in >90% of children. The ceftriaxone potent activity M. tuberculosis could potentially shorten therapy in children with disseminated TB.
Ceftazidime-avibactam is an effective agent for the treatment of tuberculosis (TB) but requires frequent administration because of a short half-life. Due to a longer half-life, ceftriaxone could allow intermittent dosing.
Methods:
First, we identified the MIC of ceftriaxone with 15 mg/L avibactam in 30 clinical Mycobacterium tuberculosis isolates. Next, 2 ceftriaxone exposure-effect studies in the intracellular hollow fiber model of TB (HFS-TB) that mimics disseminated disease in young children, were performed. Ceftriaxone was administered once or twice daily for 28 days to explore percentage of time that the concentration persisted above MIC (%TMIC) ranging from 0 to 100%. In a third HFS-TB experiment, the “double cephalosporin” regimen of ceftazidime-ceftriaxone-avibactam was examined and analyzed using Bliss Independence.
Conclusion:
The MIC99 of the clinical strains was 32 mg/L, in the presence of 15 mg/L avibactam. Ceftriaxone %TMIC <42 had no microbial effect in the HFS-TB, %TMIC>54% demonstrated a 4.1 log10 colony-forming units per milliliter M. tuberculosis kill, while %TMIC mediating Emax was 68%. The “double cephalosporin” combination was highly synergistic. Monte Carlo experiments of 10,000 subjects identified the optimal ceftriaxone dose as 100 mg/kg twice a day.
Conclusion:
The combination of ceftriaxone-avibactam at 100 mg/kg could achieve Emax in >90% of children. The ceftriaxone potent activity M. tuberculosis could potentially shorten therapy in children with disseminated TB.
Date Issued
2020-12
Date Acceptance
2020-07-22
Citation
The Pediatric Infectious Disease Journal, 2020, 39 (12), pp.1092-1100
ISSN
0891-3668
Publisher
Lippincott, Williams & Wilkins
Start Page
1092
End Page
1100
Journal / Book Title
The Pediatric Infectious Disease Journal
Volume
39
Issue
12
Copyright Statement
© 2020 Lippincott Williams & Wilkins, Inc. This is a non-final version of an article published in final form in The Pediatric Infectious Disease Journal: August 5, 2020 - Volume Online First - Issue - doi: 10.1097/INF.0000000000002857
Identifier
https://journals.lww.com/pidj/Fulltext/2020/12000/Evaluation_of_Ceftriaxone_Plus_Avibactam_in_an.14.aspx
Subjects
1114 Paediatrics and Reproductive Medicine
1117 Public Health and Health Services
Pediatrics
Publication Status
Published online
Date Publish Online
2020-08-05