Colistin and Polymyxin B Dosage Regimens against Acinetobacter baumannii: Differences in Activity and the Emergence of Resistance

Abstract

Infections caused by multidrug-resistant Acinetobacter baumannii are a major public health problem, and polymyxins are often the last line of therapy for recalcitrant infections by such isolates. The pharmacokinetics of the two clinically used polymyxins, polymyxin B and colistin, differ considerably, since colistin is administered as an inactive prodrug that undergoes slow conversion to colistin. However, the impact of these substantial pharmacokinetic differences on bacterial killing and resistance emergence is poorly understood. We assessed clinically relevant polymyxin B and colistin dosage regimens against one reference and three clinical A. baumannii strains in a dynamic one-compartment in vitro model. A new mechanism-based pharmacodynamic model was developed to describe and predict the drug concentrations and viable counts of the total and resistant populations. Rapid attainment of target concentrations was shown to be critical for polymyxin-induced bacterial killing. All polymyxin B regimens achieved peak concentrations of at least 1 mg/liter within 1 h and caused ≥4 log10 killing at 1 h. In contrast, the slow rise of colistin concentrations to 3 mg/liter over 48 h resulted in markedly reduced bacterial killing. A significant (4 to 6 log10 CFU/ml) amplification of resistant bacterial populations was common to all dosage regimens. The developed mechanism-based model explained the observed bacterial killing, regrowth, and resistance. The model also implicated adaptive polymyxin resistance as a key driver of bacterial regrowth and predicted the amplification of preexisting, highly polymyxin-resistant bacterial populations following polymyxin treatment. Antibiotic combination therapies seem the most promising option for minimizing the emergence of polymyxin resistance.

FIG 1

Concentration-time profiles for colistin base (A) and polymyxin B base (B to D) of simulated (t_1/2 = 11.6 h, C_ss,avg = 3 mg/liter) clinically relevant polymyxin dosage regimens. (A) Gradual rise of colistin (as seen in patients following CMS administration); (B) polymyxin B, 1-h infusion every 12 hours with no loading dose; (C) polymyxin B, 1-h infusion every 12 hours with a conventional loading dose; (D) polymyxin B, 1-h infusion every 12 hours with an augmented loading dose.

FIG 2

Model structure of the developed mechanism-based model for polymyxin-mediated bacterial killing and the dynamics of constitutive and adaptive polymyxin resistance. The washout of bacteria from the IVM has not been included in this diagram for clarity.

FIG 3

Observed data (points) and individual model fits (lines) for total viable bacteria (■ and thick solid line), resistant bacteria (▲ and thick dashed line), and polymyxin concentrations (◆, dotted line) for control (A), gradual rise of colistin (R1) (B), polymyxin B with no loading dose (R2) (C), a conventional loading dose (R3) (D), and augmented loading dose (R4) (E) against A. baumannii strain ATCC 19606.

FIG 4

Observed data (points) and individual model fits (lines) for total viable bacteria (■ and thick solid line), resistant bacteria (▲ and thick dashed line), and polymyxin concentrations (◆, dotted line) for control (A), gradual rise of colistin (R1) (B), polymyxin B with no loading dose (R2) (C), a conventional loading dose (R3) (D), and augmented loading dose (R4) (E) against A. baumannii strain AB307-0294.

FIG 5

Observed data (points) and individual model fits (lines) for total viable bacteria (■ and thick solid line), resistant bacteria (▲ and thick dashed line), and polymyxin concentrations (◆, dotted line) for control (A), gradual rise of colistin (R1) (B), polymyxin B with no loading dose (R2) (C), a conventional loading dose (R3) (D), and augmented loading dose (R4) (E) against A. baumannii strain FADDI-AB008.

FIG 6

Observed data (points) and individual model fits (lines) for total viable bacteria (■ and thick solid line), resistant bacteria (▲ and thick dashed line), and polymyxin concentrations (◆, thick dotted line) for control (A), gradual rise of colistin (R1) (B), polymyxin B with no loading dose (R2) (C), a conventional loading dose (R3) (D), and augmented loading dose (R4) (E) against A. baumannii strain FADDI-AB030.

FIG 7

Model simulation results for A. baumannii strain AB307-0294 (initial inoculum, 10⁶ CFU/ml) treated with unbound concentration-time profiles adapted from population PK studies (8, 9) of colistin following CMS administration in a patient with normal renal function (360 mg colistin base activity loading dose, 140 mg every 12 h maintenance dose) (A) and a polymyxin B dosage regimen representing the 50th percentile of critically ill patients receiving a 2-mg/kg polymyxin B loading dose, followed by 1.25 mg/kg every 12 h (C). The dynamics of initially susceptible (adaptive resistance) (solid line) and constitutively resistant (dashed line) bacterial populations are shown separately (B and D).