Triple combination of meropenem, colistin and tigecycline was bactericidal in a dynamic model despite mere additive interactions in chequerboard assays against carbapenemase-producing Klebsiella pneumoniae isolates.

Abstract

Combination schemes are commonly used for the treatment of infections due to carbapenemase-producing Klebsiella pneumoniae (CP-Kp). We therefore investigated the in vitro effectiveness of double and triple combinations of meropenem, colistin and tigecycline against CP-Kp isolates with different resistance mechanisms in a static broth microdilution model and a pharmacokinetic-pharmacodynamic model. One WT isolate and seven CP-Kp isolates with different carbapenem resistance mechanisms and increasing MICs of meropenem (4-512 mg/L), colistin (0.5-32 mg/L) and tigecycline (0.25-4 mg/L) were tested with a 3D chequerboard microdilution method. Combinations were then assessed in an in vitro pharmacokinetic-pharmacodynamic model simulating 50 and 100 mg of tigecycline q12h as a 1 h infusion, 4.5 million units of colistin q12h as a 1 h infusion and 1 g of meropenem q8h as 1 and 0.5 h infusions for 2 days. In the chequerboard assay, interactions within the triple combination were mainly additive with a median (range) fractional inhibitory index of 0.66 (0.22-1.26). In the dynamic model, meropenem alone was bactericidal against isolates with MICs up to 4 mg/L, whereas bactericidal activity was found with the double combination meropenem + colistin and the triple combination meropenem + colistin + tigecycline against CP-Kp isolates with meropenem MICs of 16 and 256 mg/L, respectively. A high dose (100 mg) of tigecycline and a prolonged infusion (1 h) of meropenem increased the efficacy of the triple combination. Despite the merely additive interactions in the chequerboard assay, the triple combination of meropenem, tigecycline and colistin was bactericidal in the dynamic model against highly resistant CP-Kp isolates. This effect was more pronounced if prolonged infusion of meropenem and high tigecycline dosing were used.