fAUC/MIC is the most predictive pharmacokinetic/pharmacodynamic index of colistin against Acinetobacter baumannii in murine thigh and lung infection models

Abstract

Objectives: To elucidate the pharmacokinetic/pharmacodynamic (PK/PD) index that predicts colistin efficacy against Acinetobacter baumannii in neutropenic murine thigh and lung infection models, and to determine the extent of the emergence of resistance in vivo to colistin.

Methods: PK/PD of colistin was studied in thigh and lung infection models against A. baumannii ATCC 19606 and two multidrug-resistant clinical isolates (two of the three strains were colistin heteroresistant). Dose fractionation studies were conducted over a daily dose range of 1-160 mg/kg colistin sulphate. Bacterial burden in tissues was measured at 24 h. Non-linear least squares regression analyses were employed to determine the PK/PD index (fAUC/MIC, fC(max)/MIC or fT(>MIC)) best correlating with the efficacy of colistin in each model. Real-time population analysis profiles were conducted for tissue samples to monitor the emergence of resistance.

Results: The fAUC/MIC was the PK/PD index that correlated best with efficacy in both thigh (R(2) = 0.90) and lung (R(2) = 0.80) infection models. The fAUC/MIC targets required to achieve stasis and 1 log kill against the three strains were 1.89-7.41 and 6.98-13.6 in the thigh infection model, respectively, while the corresponding values were 1.57-6.52 and 8.18-42.1 in the lung infection model. Amplification of colistin-resistant subpopulations was revealed for all strains in both models after 24 h colistin treatment.

Conclusions: This study indicates the importance of achieving adequate time-averaged exposure to colistin and defined target fAUC/MIC values for various magnitudes of kill. Amplification of resistant subpopulations indicates the importance of investigating rational combinations with colistin. The results will facilitate efforts to optimize colistin use in humans.

Figure 1

Relationships for A. baumannii ATCC 19606 between the log₁₀ cfu/thigh at 24 h and the PK/PD indices (a) fAUC/MIC, (b) fC_max/MIC and (c) fT_>MIC. Each symbol represents the mean datum per mouse from two thighs. R² is the coefficient of determination. The dotted line represents the mean bacterial burden in thighs at the start of treatment.

Figure 2

Percentage of the total bacterial population able to grow at each colistin concentration (0.5, 1, 2, 3, 4, 5, 6, 8 and 10 mg/L) on the PAP plates (relative to colistin-free plates) determined from real-time PAPs of thigh (T) and lung (L) samples of (1) ATCC 19606, (2) 248-01-C.248 and (3) N-16870.213 after exposure to selected dosage regimens of colistin for 24 h or no colistin treatment in the PD study. Corresponding data for the respective inocula are also shown. The numbers in parentheses in the symbol keys are the log₁₀ cfu per thigh or lung, or log₁₀ cfu/mL for the inocula. Data missing for certain colistin concentrations correspond to values below the limit of bacterial counting.