In Vitro Activity of Ceftazidime-Avibactam Alone and in Combination with Amikacin Against Colistin-Resistant Gram-Negative Pathogens

Aims: Colistin became the critical treatment option for multidrug-resistant Gram-negative bacteria (GNB); however, resistance to colistin is increasingly being reported among clinical isolates. New therapy strategies should be considered nowadays. The aim of this study was to investigate the in vitro activity of a novel β-lactam/β-lactamases inhibitor ceftazidime-avibactam (CZA) alone and in combination with amikacin against colistin-resistant Gram-negative pathogens. Results: Among all the colistin-resistant GNB strains, 30.4% (21/69) were resistant to CZA, which was similar to the resistance rate of 25.4% (35/138) in colistin-susceptible strains (p > 0.05), displaying a relatively lower resistance rate compared with other antimicrobial agents (except amikacin). A majority of CZA-resistant GNB isolates (33/56) produced NDM carbapenemase. The fractional inhibitory concentration index method revealed synergistic (47.6%, 10/21) or additive (52.4%, 11/21) effects of CZA in combination with amikacin against colistin- and CZA-resistant GNB isolates, wherein the synergistic activity was found against all tested Klebsiella pneumoniae isolates (four) and Pseudomonas aeruginosa isolates (two). The time-killing curve assay verified the synergistic activity of CZA and amikacin in K. pneumoniae (FK2778) and P. aeruginosa (TL2294). The susceptible breakpoint index values showed that CZA in combination with amikacin reduced the MIC to less than the susceptibility breakpoint among 71.4% (15/21) of all tested strains. Conclusion: CZA may be a new alternative for colistin-resistant Gram-negative infections and pending clinical studies combining CZA with amikacin should be considered against these pathogens, particularly for K. pneumoniae and P. aeruginosa.