The combination of colistin and fosfomycin is synergistic against NDM-1-producing Enterobacteriaceae in in vitro pharmacokinetic/pharmacodynamic model experiments

• We studied the interaction of colistin and fosfomycin against NDM-1-producing Enterobacteriaceae.
• We used both time–kill curve studies and in vitro pharmacodynamic model experiments.
• Combination of colistin and fosfomycin showed antimicrobial additivity and synergy.
• Combination of colistin and fosfomycin reduced the chance of emergence of resistance.
• There was no evidence of antagonism even against fosfomycin-resistant isolates.

The chemotherapeutic options against NDM-1-producing Enterobacteriaceae infections are limited and therefore combination therapy is gaining momentum to counter the secondary resistance and potential suboptimal efficacy of monotherapy. Colistin and fosfomycin are two separate classes of antimicrobial agents that act on bacterial cells by different mechanisms. Hence, there is a potential for both synergy and antagonism. In this study, the antibacterial effects (ABEs) of colistin and fosfomycin were systematically investigated by time–kill curve studies over 48 h as well as in an in vitro pharmacokinetic model over 96 h against six well characterised strains of NDM-1-producing Enterobacteriaceae (three isolates resistant and three susceptible to fosfomycin) at a standard inoculum of 106 CFU/mL. Clinically achievable free serum concentrations of colistin sulphate and fosfomycin were used. In a single-chamber in vitro model, peak/trough concentrations (Cmax/Cmin) and the half-life (t1/2) for fosfomycin (250/40 mg/L and 2.7 h, respectively) and colistin sulphate (3.0/0.75 mg/L and 4 h, respectively) were used, along with a growth control. ABEs were measured by the decrease in viable bacterial counts (log kill), area under the bacterial kill curve (AUBKC) and population analysis profile (PAP). The combination of colistin and fosfomycin compared with either agent alone achieved increased bacterial killing and decreased the chance of emergence of resistance. Also, the ABEs of the combination were sustained for a longer duration and were evident both against fosfomycin-sensitive and -resistant strains. This study provides important information and support for the role of combination therapy against multidrug-resistant Gram-negative bacteria with limited therapeutic options.