ABSTRACT
Antimicrobial resistance (AMR) in
Acinetobacter baumannii
is an unmet medical need. Multiple drug-resistant/extremely drug-resistant strains of
A. baumannii
do not display growth well in
in vivo
models, and consequently, their response to antibacterial therapy is inconsistent. We addressed this issue by engineering carbapenem resistance motifs into the highly virulent genetic background of
A. baumannii
AB5075. This strain has a chromosomally encoded
oxa-23
that was deleted (
Δoxa-23
), then plasmids expressing
oxa-23
,
oxa-24/40
,
oxa-58
,
imp-1
,
vim-2
, and
ndm-1
were introduced to create the mutant strains. Each transformant was used as a challenge strain in a neutropenic murine thigh infection model and assessed for the extent of growth and response to meropenem 200 mg/kg subcutaneously every 6 h (q6h). Pharmacodynamic analyses were performed by transforming drug exposure from dose (mg/kg) to the fraction of the dosing interval; free meropenem concentrations were >minimum inhibitory concentration (MIC) (
f
T > MIC). AB5075 and the AB5075
Δoxa-23
mutant had a MICs of 32 and 4 mg/L, respectively. The transformants harboring oxacillinases
oxa-24/40
and
oxa-58
had an MIC of 64 mg/L. The metallo-β-lactamases
imp-1
,
vim-2
, and
ndm-1
had MICs of 128, 64, and 64 mg/L, respectively. All vehicle-treated transformants displayed
in vivo
growth in the range of 0.75–1.4 log. The response to meropenem was consistent with the varying
f
T > MIC of the transformants and was readily described by an inhibitory sigmoid
Emax
relationship. Stasis was achieved with a
f
T > MIC of 0.36. These
A. baumannii
transformants are invaluable new tools for the assessment of anti-
Acinetobacter
compounds and provide a new pathway for AMR preparedness.