Synergistic activity of ceftazidime-avibactam in combination with polymyxin B against carbapenem-resistant Klebsiella pneumoniae
Borjan J1, Meyer, KA1, Wenzler E1
1University of Illinois at Chicago, Chicago, IL, USA
Background: Combination antimicrobial therapy is often recommended for the treatment of serious infections due to carbapenem-resistant Klebsiella pneumoniae (CRKP). Demonstrating synergy between ceftazidime-avibactam (C-A) and other antimicrobials in vitro may help elucidate the rate, magnitude, and duration of bactericidal activity and suggest combinations that may be effective in the clinical arena.
Methods: 3 clinical CRKP were used for all experiments. C-A and polymyxin B (PB) MICs and time-kill analyses were performed in triplicate according to CLSI guidelines. Individual drugs were tested at ¼, ½, 1, 2, 4x MIC. A ≥3 log10 CFU/mL reduction compared to the starting inoculum (106) was considered bactericidal. Synergy was assessed by testing combinations at the highest concentration of each drug that showed no activity alone and was defined as ≥2 log10 CFU/mL increase in killing at 24h with the combination compared to most active agent alone.
Results: MICs: C-A 1, 8, 16 mg/L; PB 0.25, 0.25, 64 mg/L. C-A alone was bactericidal against all strains at 4x MIC (mean 24h bacterial reduction of 3.42 log10 CFU/mL). PB at 4x MIC was bactericidal for all strains at 6h (mean bacterial reduction of 3.58 log10 CFU/mL) but regrowth to control levels was seen at 24h. C-A alone at ½x MIC and combinations at ½x MIC for strains KPC1 and KPC2 yielded minimal killing followed by regrowth (mean 24h total bacterial count of 8.77 log10 CFU/mL). In contrast, bactericidal activity was observed at 24h with C-A alone at ½x MIC and in combination at ½x MIC (3.14 and 3.62 log10 CFU/mL reduction, respectively) for strain KPC3. Synergy was not observed for any isolate at the concentrations tested.
Conclusion: C-A demonstrated concentration-dependent bactericidal activity against all CRKP whereas PB showed initial bactericidality followed by regrowth and development of resistance. The combination of C-A and PB was not synergistic against C-A and PB susceptible or resistant CRKP isolates. Our data does not support the use of ceftazidime-avibactam in combination with polymyxin B for CRKP.