Amikacin activity against carbapenem-resistant Klebsiella pneumoniae without phenotypic aminoglycoside resistance: impact of aminoglycoside-modifying enzyme (AME) gene aac(6′)-Ib-cr in vitro and in vivo
Abstract
Objectives: Aminoglycosides are often combined with β-lactams for the treatment of carbapenem-resistant Enterobacterales, but the impact of aminoglycoside-modifying enzyme (AME) genes on treatment efficacy in phenotypically susceptible isolates remains unclear. We evaluated whether aac(6′)-Ib-cr, the AME gene with recognized activity against amikacin, attenuates amikacin efficacy in KPC-producing Klebsiella pneumoniae.
Methods: Thirteen clinical isolates of KPC-producing K. pneumoniae without phenotypic aminoglycoside resistance (amikacin MIC ≤4 mg/L; median 2, range 0.5–3 mg/L) were studied. Three were AME-negative; 10 were AME-positive, carrying aac(6′)-Ib-cr, aac(3)-IIa and strA/strB. Amikacin activity was assessed by time-kill assays and a Galleria mellonella survival model, compared with ceftazidime–avibactam.
Results: In time-kill assays, amikacin killing at 24 h was greater in AME-negative isolates than in AME-positive isolates (mean 4.28 ± 1.30 versus 2.41 ± 2.16 log10 cfu/mL), with more regrowth by 72 h in AME-positive isolates (median 1.94 [0–5.82] versus 0 [0–3.32] log10). In the survival model, amikacin reduced larval mortality versus saline (HR, 0.32; 95% CI, 0.24–0.43; P < 0.001). The interaction between AME-positive status and amikacin (HR, 2.11; 95% CI, 1.54–2.90; P < 0.001) indicated reduced efficacy that persisted after adjustment for amikacin MIC (adjusted HR, 2.09; 95% CI, 1.52–2.86; P < 0.001). Ceftazidime–avibactam reduced mortality (HR, 0.24; 95% CI, 0.18–0.33; P < 0.001) with no significant interaction with AME gene status (HR, 1.03; 95% CI, 0.71–1.48; P = 0.894).
Conclusion: Carriage of aac(6′)-Ib-cr was associated with reduced amikacin efficacy despite phenotypic susceptibility, independently of amikacin MIC, consistent with a treatment effect modifier rather than a binary resistance determinant. Genotyping of aac(6′)-Ib-cr may help guide aminoglycoside use in carbapenem-resistant Klebsiella pneumoniae infections.
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BibTeX
@article{kim2026amikacin,
title = {{Amikacin activity against carbapenem-resistant Klebsiella pneumoniae without phenotypic aminoglycoside resistance: impact of aminoglycoside-modifying enzyme (AME) gene aac(6′)-Ib-cr in vitro and in vivo}},
author = {Jaehoon Kim and Jae Eun Seong and Youn-Jung Lee and Sora Park and Min Han and Yongseop Lee and Jung Ah Lee and Jung Ho Kim and Jin Young Ahn and Su Jin Jeong and Nam Su Ku and Joon-Sup Yeom and Hyukmin Lee and Jun Yong Choi},
journal = {JAC-antimicrobial resistance},
year = {2026},
month = nov,
doi = {10.1093/jacamr/dlag239},
url = {https://europepmc.org/article/PMC/PMC13724272},
note = {CC BY},
}
RIS
TY - JOUR
TI - Amikacin activity against carbapenem-resistant Klebsiella pneumoniae without phenotypic aminoglycoside resistance: impact of aminoglycoside-modifying enzyme (AME) gene aac(6′)-Ib-cr in vitro and in vivo
AU - Jaehoon Kim
AU - Jae Eun Seong
AU - Youn-Jung Lee
AU - Sora Park
AU - Min Han
AU - Yongseop Lee
AU - Jung Ah Lee
AU - Jung Ho Kim
AU - Jin Young Ahn
AU - Su Jin Jeong
AU - Nam Su Ku
AU - Joon-Sup Yeom
AU - Hyukmin Lee
AU - Jun Yong Choi
PY - 2026
DA - 2026/11/02
JO - JAC-antimicrobial resistance
DO - 10.1093/jacamr/dlag239
UR - https://europepmc.org/article/PMC/PMC13724272
AB - Objectives: Aminoglycosides are often combined with β-lactams for the treatment of carbapenem-resistant Enterobacterales, but the impact of aminoglycoside-modifying enzyme (AME) genes on treatment efficacy in phenotypically susceptible isolates remains unclear. We evaluated whether aac(6′)-Ib-cr, the AME gene with recognized activity against amikacin, attenuates amikacin efficacy in KPC-producing Klebsiella pneumoniae. Methods: Thirteen clinical isolates of KPC-producing K. pneumoniae without phenotypic aminoglycoside resistance (amikacin MIC ≤4 mg/L; median 2, range 0.5–3 mg/L) were studied. Three were AME-negative; 10 were AME-positive, carrying aac(6′)-Ib-cr, aac(3)-IIa and strA/strB. Amikacin activity was assessed by time-kill assays and a Galleria mellonella survival model, compared with ceftazidime–avibactam. Results: In time-kill assays, amikacin killing at 24 h was greater in AME-negative isolates than in AME-positive isolates (mean 4.28 ± 1.30 versus 2.41 ± 2.16 log10 cfu/mL), with more regrowth by 72 h in AME-positive isolates (median 1.94 [0–5.82] versus 0 [0–3.32] log10). In the survival model, amikacin reduced larval mortality versus saline (HR, 0.32; 95% CI, 0.24–0.43; P < 0.001). The interaction between AME-positive status and amikacin (HR, 2.11; 95% CI, 1.54–2.90; P < 0.001) indicated reduced efficacy that persisted after adjustment for amikacin MIC (adjusted HR, 2.09; 95% CI, 1.52–2.86; P < 0.001). Ceftazidime–avibactam reduced mortality (HR, 0.24; 95% CI, 0.18–0.33; P < 0.001) with no significant interaction with AME gene status (HR, 1.03; 95% CI, 0.71–1.48; P = 0.894). Conclusion: Carriage of aac(6′)-Ib-cr was associated with reduced amikacin efficacy despite phenotypic susceptibility, independently of amikacin MIC, consistent with a treatment effect modifier rather than a binary resistance determinant. Genotyping of aac(6′)-Ib-cr may help guide aminoglycoside use in carbapenem-resistant Klebsiella pneumoniae infections.
SN - 2632-1823
ER -