Efficacy of ceftazidime-avibactam in various combinations for the treatment of experimental osteomyelitis due to Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae

Background: : Optimal treatment of carbapenemase-producing Enterobacterales (CPE) bone infections is poorly defined. This study evaluated the efficacy of the novel beta-lactam-beta-lactamase inhibitor- ceftazidime-avibactam (CAZ-AVI)-with different antibiotic combinations in an experimental model of CPE osteomyelitis.Methods: : KPC-99YC is a clinical strain of Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae with intermediate susceptibility to meropenem (MIC 4 mg/L), gentamicin (MIC 0.25 mg/L), colistin (MIC 0.25 mg/L), fosfomycin (MIC 4 mg/L) and ceftazidime-avibactam (MIC 1 mg/L). Timekill curves were performed at 4x MIC. Osteomyelitis was induced in rabbits by tibial injection of 2 x10(8) CFU of KPC-99YC. Six groups started treatment 14 days later for 7 days: control, colistin, CAZ-AVI, CAZ-AVI plus gentamicin, CAZ-AVI plus colistin and CAZ-AVI plus fosfomycin. Antibiotic dosages were selected to simulate plasma concentrations obtained in humans. Treatment was evaluated according to bone cultures quantified in log( 10) CFU.Results: : In vitro, CAZ-AVI plus colistin or gentamicin were rapidly bactericidal in contrast with CAZAVI plus f osf omycin. In vivo, compared with controls, colistin alone ( P = 0.045) and CAZ-AVI alone or in combination significantly lowered bone bacterial counts ( P < 0.001). Bone sterilisation was achieved in 67% and 100% of animals with combinations of CAZ-AVI plus colistin or gentamicin ( P = 0.001 and P < 0.001, respectively) whereas other treatments were no different from controls. CAZ-AVI plus gentamicin provided greater bone bacterial reduction than CAZ-AVI plus colistin ( P = 0.033). No CAZ-AVI-resistant strains emerged in treated rabbits, regardless of combination.Conclusions: : CAZ-AVI plus gentamicin was the best effective combination therapy. Combinations with CAZ-AVI appear to be a promising treatment of KPC-producing Klebsiella pneumoniae osteomyelitis.(c) 2022 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.