2451. Synergistic Activity of Ceftazidime–Avibactam in Combination With Polymyxin B Against Carbapenem-Resistant Klebsiella pneumoniae

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: Three 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 log(10) CFU/mL reduction compared with the starting inoculum (10(6)) 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 log(10) CFU/mL increase in killing at 24 hours with the combination compared with 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 4× MIC (mean 24 hours bacterial reduction of 3.42 log(10) CFU/mL). PB at 4× MIC was bactericidal for all strains at 6 hours (mean bacterial reduction of 3.58 log(10) CFU/mL) but regrowth to control levels was seen at 24 hours. C-A alone at ½× MIC and combinations at ½× MIC for strains KPC1 and KPC2 yielded minimal killing followed by regrowth (mean 24 hours total bacterial count of 8.77 log(10) CFU/mL). In contrast, bactericidal activity was observed at 24h with C-A alone at ½× MIC and in combination at ½× MIC (3.14 and 3.62 log(10) 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 do not support the use of ceftazidime–avibactam in combination with polymyxin B for CRKP. DISCLOSURES: E. Wenzler, Melinta Therapeutics: Speaker’s Bureau, Speaker honorarium.