Objectives: To study the in vitro synergistic bactericidal activity of dual β-
lactam antibiotics against KPC-2-producing Klebsiella pneumoniae and to explore the new therapeutic regimens for
infections caused by
carbapenem-resistant strains. Materials and Methods: The antimicrobial susceptibility testing of
imipenem,
meropenem,
ceftazidime, and
clavulanic acid on 40 clinically isolated strains of KPC-2-producing K. pneumoniae from 5 cities across the country was performed by microdilution broth method. The in vitro synergistic bactericidal activity of combined
antibiotics mentioned above was determined at various concentrations using checkerboard techniques. The combination of
antibiotics include
imipenem with
clavulanic acid,
meropenem with
clavulanic acid,
imipenem with
ceftazidime,
meropenem with
ceftazidime, and
meropenem with
imipenem. The combined effectiveness of synergistic, indifferent, or antagonistic was calculated by fractional inhibitory concentration indexes. Based on the results of synergistic bactericidal activity, 16 strains were selected for time-kill assays. Results: All 40 strains of K. pneumoniae were shown resistant to every single
antimicrobial agent tested, with minimal inhibitory concentrations of
carbapenems >32 mg/L in most isolates. None of the combinations was antagonistic. Synergies of combination of
imipenem with
clavulanic acid, or
imipenem with
ceftazidime were observed in 80% (32/40) and 7.5% (3/40) of strains, respectively; Combinations of
meropenem and
clavulanic acid, or
meropenem and
ceftazidime revealed a synergistic antibacterial activity on 25% (10/40) and 30% (12/40) of strains, respectively. Synergy of
meropenem and
imipenem combination was shown in 30% (12/40) of strains. Time-kill assays validated the data from checkerboard testing. Conclusions: The study strongly supported the hypothesis that combined dual β-
lactam antibiotics might be effective in the treatment of
infections caused by KPC-2-producing K. pneumoniae. The combination of
imipenem and
clavulanic acid possessed the best efficiency, followed by the regimens of combined
meropenem-
ceftazidime and
imipenem-
meropenem.