Drug design, development and therapy · 2026
In vitro Screening for Synergistic Polymyxin B-Based Combinations Against KPC- Producing Carbapenem-Resistant Klebsiella pneumoniae.
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Lv Menghan, Yi Hanxi, Liu Yalan, Xie Yehua, Cheng Zeneng, Xie Feifan, Li Sanwang
Аннотация
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.
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.