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Published on: April 18, 2019
In vitro Screening for Synergistic Polymyxin B-Based Combinations Against KPC- Producing Carbapenem-Resistant
Menghan Lv1, Hanxi Yi2, Yalan Liu1
1Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, People's Republic of China.
Objective:
Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections often necessitate combination therapy, yet effective treatment options remain limited. This study aimed to evaluate the bactericidal effects of polymyxin B-based combination therapy with ten representative antibiotics against KPC-producing CRKP.
Methods:
Phenotypic and genotypic analyses were performed on clinically CRKP isolates. Susceptibility of KPC-producing strains was assessed via broth microdilution. Ten heterogeneous isolates were selected for 24-hour static time-kill assays to evaluate the bactericidal activity of polymyxin B and ten antibiotics (tigecycline, minocycline, meropenem, imipenem, doripenem, amikacin, fosfomycin, aztreonam, ceftazidime, and cefepime)-both as monotherapies and in combination with polymyxin B. Additionally, 24-hour time-course kill studies were conducted for a representative polymyxin B-based combination against a polymyxin B-resistant strain using clinically relevant concentration matrices.
Results:
Among 22 CRKP isolates, 16 consistently produced KPC enzymes and carried the bla KPC-2 gene. Of the 10 selected KPC-producing strains, polymyxin B susceptibility was classified as 2 susceptible, 4 intermediate, and 4 resistant. All monotherapies, including polymyxin B, showed limited efficacy. Notable synergistic activity was observed when polymyxin B was combined with tigecycline (8/10), imipenem (7/10), ceftazidime (9/10), or cefepime (9/10), while other combinations were largely ineffective. A 24-hour time-course kill assay using polymyxin B plus ceftazidime as a representative demonstrated that synergy was concentration-dependent and could be rapidly achieved at clinical concentration combinations.
Conclusion:
This study demonstrated that combinations of polymyxin B with tigecycline, imipenem, ceftazidime, or cefepime show promising therapeutic potential against KPC-producing CRKP. Further studies are warranted to evaluate their in vivo efficacy.
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