Synergistic activity of colistin and rifampin combination against multidrug-resistant Acinetobacter baumannii in an in vitro pharmacokinetic/pharmacodynamic model

Abstract

Combination therapy may be required for multidrug-resistant (MDR) Acinetobacter baumannii. This study systematically investigated bacterial killing and emergence of colistin resistance with colistin and rifampin combinations against MDR A. baumannii. Studies were conducted over 72 h in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model at inocula of ~10(6) and ~10(8) CFU/ml using two MDR clinical isolates of A. baumannii, FADDI-AB030 (colistin susceptible) and FADDI-AB156 (colistin resistant). Three combination regimens achieving clinically relevant concentrations (constant colistin concentration of 0.5, 2, or 5 mg/liter and a rifampin maximum concentration [C(max)] of 5 mg/liter every 24 hours; half-life, 3 h) were investigated. Microbiological response was measured by serial bacterial counts. Population analysis profiles assessed emergence of colistin resistance. Against both isolates, combinations resulted in substantially greater killing at the low inoculum; combinations containing 2 and 5 mg/liter colistin increased killing at the high inoculum. Combinations were additive or synergistic at 6, 24, 48, and 72 h with all colistin concentrations against FADDI-AB030 and FADDI-AB156 in, respectively, 8 and 11 of 12 cases (i.e., all 3 combinations) at the 10(6)-CFU/ml inoculum and 8 and 7 of 8 cases with the 2- and 5-mg/liter colistin regimens at the 10(8)-CFU/ml inoculum. For FADDI-AB156, killing by the combination was ~2.5 to 7.5 and ~2.5 to 5 log(10) CFU/ml greater at the low inoculum (all colistin concentrations) and high inoculum (2 and 5 mg/liter colistin), respectively. Emergence of colistin-resistant subpopulations was completely suppressed in the colistin-susceptible isolate with all combinations at both inocula. Our study provides important information for optimizing colistin-rifampin combinations against colistin-susceptible and -resistant MDR A. baumannii.

Fig 1

(Left) Time-kill curves with various clinically relevant dosage regimens of colistin (Col) and rifampin (Rif) alone and in combination at an inoculum of ∼10⁶ CFU/ml. (Right) PAPs at baseline (0 h) and after 72 h of exposure to colistin monotherapy, colistin-rifampin combination therapy, or neither antibiotic (control). (A) FADDI-AB030 (colistin susceptible, rifampin resistant, MDR); (B) FADDI-AB156 (colistin resistant, rifampin resistant, MDR). The y axis starts from the limit of detection, and the limit of quantification is indicated by the dashed horizontal line.

Fig 2

(Left) Time-kill curves with various clinically relevant dosage regimens of colistin (Col) and rifampin (Rif) alone and in combination at an inoculum of ∼10⁸ CFU/ml. (Right) PAPs at baseline (0 h) and after 72 h of exposure to colistin monotherapy, colistin-rifampin combination therapy, or neither antibiotic (control). (A) FADDI-AB030 (colistin susceptible, rifampin resistant, MDR); (B) FADDI-AB156 (colistin resistant, rifampin resistant, MDR). The y axis starts from the limit of detection, and the limit of quantification is indicated by the dashed horizontal line.