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. 2024 Dec 23:17:5785-5794.
doi: 10.2147/IDR.S473546. eCollection 2024.

The in vitro Activity of Omadacycline Alone and in Combination Against Carbapenem-Resistant Klebsiella pneumoniae

Yingying Du #  1   2   3 , Yan Liu #  4 , Tong Liu  1 , Fen Pan  5 , Shikui Mu  2 , Yunlou Zhu  2 , Hanlu Gao  2 , Xin Jing  2 , Xing Wang  6 , Yuhao Liu  2 , Sheng Wang  1   2   3
Affiliations

The in vitro Activity of Omadacycline Alone and in Combination Against Carbapenem-Resistant Klebsiella pneumoniae

Yingying Du et al. Infect Drug Resist. .

Abstract

Objective: This study aimed to evaluate the in vitro activity of omadacycline (OMC) and OMC-based combination therapy against carbapenem-resistant Klebsiella pneumoniae (CRKP).

Methods: The broth microdilution assay assessed the in vitro susceptibility of CRKP to OMC. The checkerboard assay was performed to evaluate the activity of OMC combined with polymyxin B (PB), amikacin (AN), or meropenem (MEM) against KPC-producing (class A) CRKP strains, and OMC combined with PB, aztreonam (ATM), MEM, or AN against class B and class A plus class B CRKP strains. Synergistic effects of OMC and PB were further evaluated by time-kill assays in the KPC-producing CRKP strains.

Results: Broth microdilution assays revealed a notable variation in susceptibility between KPC-producing and class B CRKP strains, with MIC50/90 of 32/32 mg/L and 0.5/8 mg/L, respectively. Although KPC-producing CRKP strains were resistant to OMC, a synergistic effect was observed in 37.5% of KPC-producing CRKP strains when OMC was combined with PB. In the nine KPC-producing CRKP strains, time-kill assays found that cell densities of six strains (66.7%) decreased by 3.61 ± 0.23 log10 CFU/mL compared to the initial inoculum after 2 hours of PB exposure. The cell densities further decreased by an average of 2.38 ± 0.23 log10 CFU/mL when the six strains were exposed to OMC plus PB, confirming their potent synergism.

Conclusion: OMC monotherapy is ineffective against KPC-producing CRKP strains, but OMC plus PB has a potent synergistic effect on them, suggesting that OMC plus PB is the preferred combination therapy against KPC-producing CRKP in vitro.

Keywords: Klebsiella pneumoniae; antibiotic combination treatment; carbapenem resistance; omadacycline; polymyxin B; time-kill test.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
The genotypic characteristics and in vitro susceptibility of 53 CRKP isolates. The first row of the grid represents the resistance genes carried by the CRKP strains, different colors represent different types of resistance genes or combinations. The second, third and fourth row of the grid represent the in vitro susceptibility of CRKP isolates against polymyxin B, omadacycline and tigecycline, respectively, and white and gray represent sensitivity and resistance, respectively. The last row of the grid represents whether omadacycline and polymyxin B have a synergistic effect, with red indicating a synergistic effect, yellow indicating an additive effect and Orange indicating an indifferent effect.
Figure 2
Figure 2
The distribution of MICs for omadacycline, tigecycline and polymyxin B in different carbapenemase types of CRKP strains. (A–C) Display the MIC value distribution of OMC, TIG, and PB in class A, class B and class A plus B CRKP isolates, respectively. OMC, TIG, PB and MIC represent omadacycline, tigecycline, polymyxin B and minimal inhibitory concentration, respectively.
Figure 3
Figure 3
(A) The time-kill curves of the 6 polymyxin B sensitive KPC-producing CRKP strains. Time-kill results for OMC, PB and OMC/PB combination against PB sensitive CRKP strains at the free maximum concentration of antibiotic in serum after antibiotics exposure for 2, 4, 6, 8, 12, 24 hours. Curves represent average concentrations from triplicate measurements. PB, OMC, GC and CFU represent polymyxin B, omadacycline, growth control and colony forming units, respectively. (B) The time-kill curves of the 3 polymyxin B resistant KPC-producing CRKP strains. Time-kill results for OMC, PB and OMC/PB combination against PB resistant CRKP strains at the free maximum concentration of antibiotic in serum after antibiotics exposure for 2, 4, 6, 8, 12, 24 hours. Curves represent average concentrations from triplicate measurements. PB, OMC, GC and CFU represent polymyxin B, omadacycline, growth control and colony forming units, respectively.
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