Methods: In the current study, 25 clinical isolates of the M. abscessus complex were compared by whole genome sequence analysis, and tested in vitro for susceptibility to CPT and IMI with or without AVI. Using a broth microdilution assay with 7H9 media, a range of drug concentrations from 0.25-128 µg/mL, was evaluated with and without AVI at a constant concentration of 4 µg/mL. On the basis of the MIC findings, we also analyzed the bactericidal activity of drug combinations against four clinical isolates (3 M. abscessus and 1 M. bolletii)in human THP-1 cells at an MOI of 1 organism to 10 cells. Bacteria were enumerated at 0, 24hr, 48hr and 72 hr post infection.
Results: WGS results distinguished the 25 M. abscessus complex into three clusters as M. massiliense, M. bolletii, and M. abscessus. Additionally, up to 16 amino acid substitutions were identified in the AmpC (blaMAB) gene. CPT MICs ranged from 0.5–128 µg/mL, but the MIC range was dramatically lowered to <0.125-16 µg/mL in the presence of AVI. IMI activity, in vitro, alone or in combination with AVI ranged from 0.5–16 µg/mL. Activity of CPT with AVI in THP-1 cells correlates with the in vitroactivity against all 4 clinical isolates, while the activity of IMI with AVI in THP-1 cells was strain dependent. Increasing concentrations of AVI was active against one strain and had no effect on another strain.
Conclusion: These findings indicate that the in vitro activity of CPT in combination with AVI is predictive for ex vivo activity in human THP-1 cells and this combination may prove to be an effective regimen in treating infections caused by M. abscessus complex.
E. Shashkina, None
C. Manca, None
R. A. Bonomo, Entasis: Grant Investigator , Research grant
Allecra: Grant Investigator , Research grant
Wockhardt: Grant Investigator , Research grant
Merck: Grant Investigator , Research grant
Roche: Grant Investigator , Research grant
GSK: Grant Investigator , Research grant
Allergan: Grant Investigator , Research grant
Shionogi: Grant Investigator , Research grant
S. G. Jenkins, Cormedix: Consultant , Consulting fee
Bayer: Consultant , Consulting fee
Merck: Grant Investigator and Scientific Advisor , Research grant
B. N. Kreiswirth, None
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