Effects of amikacin, polymyxin-B, and sulbactam combination on the pharmacodynamic indices of mutant selection against multi-drug resistant Acinetobacter baumannii

Abstract

Amikacin and polymyxins as monotherapies are ineffective against multidrug-resistant Acinetobacter baumannii at the clinical dose. When polymyxins, aminoglycosides, and sulbactam are co-administered, the combinations exhibit in vitro synergistic activities. The minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in 11 and 5 clinical resistant isolates of A. baumannii harboring OXA-23, respectively, in order to derive the fraction of time over the 24-h wherein the free drug concentration was within the mutant selection window (fT_MSW) and the fraction of time that the free drug concentration was above the MPC (fT_>MPC) from simulated pharmacokinetic profiles. The combination of these three antibiotics can confer susceptibility in multi-drug resistant A. baumannii and reduce the opportunity for bacteria to develop further resistance. Clinical intravenous dosing regimens of amikacin, polymyxin-B, and sulbactam were predicted to optimize fT_MSW and fT_>MPC from drug exposures in the blood. Mean fT_>MPC were ≥ 60% and ≥ 80% for amikacin and polymyxin-B, whereas mean fT_MSW was reduced to <30% and <15%, respectively, in the triple antibiotic combination. Due to the low free drug concentration of amikacin and polymyxin-B simulated in the epithelial lining fluid, the two predicted pharmacodynamic parameters in the lung after intravenous administration were not optimal even in the combination therapy setting.

Keywords: Acinetobacter baumannii; OXA-23; amikacin; pharmacodynamics; polymyxin-B; sulbactam.

Figure 1

Static-concentration time-kill kinetics of amikacin and polymyxin-B alone and in combination at their respective MIC and 2 × MIC and also as triple combination with 4 mg/L sulbactam against two Acinetobacter baumannii isolates. Monotherapy MICs for amikacin and polymyxin-B were >128 and 8 mg/L for isolate A, and >128 and 16 mg/L for isolate E; MICs in the double combination were 1 and 4 mg/L for isolate A and 32 and 4 mg/L for isolate E; MICs in the triple combination were 1 and 4 mg/L for isolate A and 1 and 2 mg/L for isolate E, respectively.

Figure 2

Probability of target attainment (PTA) of 60% fT_>MIC and 8 fC_max/MIC for sulbactam and amikacin dosing regimens by renal function category, respectively, and PTA of fAUC/MIC of at least 8.2 for polymyxin-B dosing regimens. PTA values were computed based on steady-state drug concentrations in the blood. LD, loading dose; CL_CR, creatinine clearance.

Figure 3

Sensitivity analysis to evaluate effect of variability in polymyxin plasma protein binding on the pharmacodynamic parameters fT_MSW and fT_>MPC after polymyxin dosing regimens in combination therapy consisting of loading dose 2.5 mg/kg followed by 1.5 mg/kg q12h at 12 h (top) and loading dose 2 mg/kg followed by 1.25 mg/kg q12h at 12 h (bottom) against Acinetobacter baumannii 20. The models assumed polymyxin-B MIC of 1 mg/L and MPC of 4 mg/L, whereas amikacin MIC and MPC were both 4 mg/L with or without 4 mg/L sulbactam. In this scenario, the proposed dosing regimens of both amikacin and sulbactam can achieve PTA ≥ 90%.

Figure 4

Probability of target attainment (PTA) of 60% fT_>MIC and 8 fC_max/MIC for sulbactam and amikacin dosing regimens by renal function category, respectively, and PTA of fAUC/MIC of at least 8.2 for polymyxin-B dosing regimens. PTA values were computed based on steady-state drug concentrations in the epithelial lining fluid and their respective epithelial lining fluid penetration. LD, loading dose; CL_CR, creatinine clearance.