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

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 KPCproducing 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.